Substituted tetrahydropyrane derivatives, method for producing same, their use as medicine or diagnostic agent, as well as medicine containing same

ABSTRACT

Substituted tetrahydropyran derivatives, processes for their preparation, their use as a pharmaceutical or diagnostic, and pharmaceutical comprising them. The invention relates to compounds of the formula I                    
     in which the radicals R 1 , R 2 , R 3 , R 4 , R 5  and X have the meaning mentioned in the description, a process for the preparation of the compounds of the formula I on a solid phase, and their use as pharmaceuticals.

This application is the National Stage filed under 35 USC 371 ofPCT/EP98/05025, filed Aug. 7, 1998.

The invention relates to substituted tetrahydropyran derivatives,processes for their preparation, their use as a pharmaceutical ordiagnostic and pharmaceutical comprising them.

Peptides and peptide mimetics are a valuable aid for the discovery ofnew lead structures and the identification of potential activecompounds. By fixing side chains in a rigid structure (scaffold), it ishoped, in comparison with the conformationally more flexible peptidechain, for an increase in the affinity of this conformationally fixedligand for the receptor.

Very different structural units are already finding use as peptidemimetics.

Owing to their polyvalency and their defined spatial arrangement,carbohydrate units should be particularly highly suitable as structuralunits for peptide mimetics.

Thus, it has recently been shown that a specific monosaccharide mimics,as a conformationally fixed structure, the spatial arrangement of acertain cyclopeptide, somatostatin (K. C. Nicolaou, J. I. Trujillo, K.Chibale, Tetrahedron 1997, 53, 8751-8778).

In this connection, starting from a glucose derivative having standardprotective groups, a restricted variation of the simply accessibleanomeric hydroxyl function and the C-6 hydroxyl function was carriedout. The synthesis strategy described there starts from already knownsugar units and is restricted by the protective group:strategy to anarrow application range of somatostatin. At the same time, the methodis not transferable to the targeted variation of the structural unit bysolid-phase synthesis.

The previous syntheses of carbohydrate derivatives in solution or in theform of substance libraries on a solid phase concentrated, inparticular, on the synthesis of oligosaccharides or glycopeptides (L.DeNapoli et al., Tetrahedron Letters 1996, 37, 5007-5010; S. J.Danishefsky et al., Science 1995, 269, 202-204, J. J. Krepinski et al.,J. Am. Chem. Soc., 1991, 113, 5095-5097).

Compounds synthesized from oligosaccharide or glycopeptide units are,however, of only very restricted use for the discovery of leadstructures or as potential active compounds on account of theircomplexity.

Restriction to a monosaccharide as a structural unit, however, combinesthe positive property of the defined spatial arrangement of the ligandswith a low complexity, low molecular weight, low toxicity and furtherproperties which are of importance for potential active compounds.

On account of the polyvalency of the monosaccharides, targeted synthesisof selectively functionalized monosaccharides—both in solution and onthe solid phase—causes great difficulties.

Variously protected carbohydrate units are likewise known as a result ofthe various studies on carbohydrate chemistry (see R. R. Schmidt, Pure &Appl. Chem. 1989, 61, 1257). In the intermediates described there, thehydroxyl groups are temporarily blocked more or less selectively byprotective groups which are then deprotected for linkage with otherprotective groups, as a result of which the synthesis of di- oroligosaccharides takes place.

These intermediates or the polysugars synthesized therefrom are,however, of only restricted use for specific lead structure discoveryand as potential active compounds. In some cases, these structures arerelatively labile and thus not resistant to degradation or cleavage.

The linkers and activation strategies developed for the preparation ofthe abovementioned polysaccharides or glycopeptides (D. Kahne et al., J.Am. Chem. Soc. 1994, 116, 6953-6954) are also not generally transferableto the preparation of selectively polysubstituted monosaccharidecompounds.

The specific synthesis of selectively functionalized monosaccharidederivatives therefore requires the development of a novel, completelyorthogonal protective group strategy, which makes it possible toselectively remove the protective groups of all functional groups, theconditions used for this being stable to the conditions of the synthesissequence. At the same time, these protective groups must guaranteecompatibility with all reaction conditions which are necessary forsynthesis in solid-phase synthesis. For synthesis on a solid phase, itis furthermore necessary to have available a linker system for linkingthe monosaccharide unit, preferably via the anomeric center, which iscompatible with all reaction conditions and can be selectivelyactivated. Such a strategy makes possible the specific differentvariation of all functionalities of the monosaccharide unit to givestable final products.

The invention thus relates to compounds of the formula I

in which:

R¹, R², R³, R⁴, R⁵ independently of one another are

1. hydrogen;

2. (C₁-C₁₂)-alkyl;

3. (C₂-C₈)-alkenyl;

4. (C₂-C₈)-alkynyl;

5. (C₁-C₆)-alkylene-(C₃-C₁₀)-cycloalkyl;

6. (C₀-C₆)-alkylene-(C₆-C₁₂)-aryl; preferably phenyl or benzyl;

7. (C₁-C₆)-alkoxy;

8. (C₀-C₆)-alkylene-CO—R⁸;

9. (C₁-C₆)-alkylene-(C₁-C₉)-heteroaryl;

10. carbamoyl;

11. —C(O)NR⁶R⁷;

12. —C(O)OR⁶;

13. a radical defined as in 2.-12., which is mono-, di- orpolysubstituted in the alkyl moiety and/or aryl or heteroaryl moiety bya radical from the group consisting of (C₁-C₆)-alkyl, NO₂, CN, halogen,CF₃ or (C₁-C₆)-alkoxy;

14. a radical defined as in 6. and 9., which is substituted in the arylor heteroaryl moiety by one, two or more halogen atoms;

R⁶ and R⁷ independently of one another are:

1. hydrogen;

2. (C₁-C₁₂)-alkyl;

3. (C₂-C₈)-alkenyl;

4. (C₂-C₈)-alkynyl;

5. (C₁-C₆)-alkylene-(C₃-C₁₀)-cycloalkyl;

6. (C₁-C₆)-alkylene-(C₆-C₁₂)-aryl; preferably benzyl;

7. (C₂-C₆)-alkyloxy;

8. (C₀-C₆)-alkylene-CO—R⁸;

9. (C₁-C₆)-alkylene-(C₁-C₉)-heteroaryl;

10. (C₀-C₆)-alkylene-(C₁-C₆)-alkoxy;

11. (C₃-C₁₀)-cycloalkyl;

12. (C₆-C₁₂)-aryl, preferably phenyl;

R⁸ is hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₂)-aryl or OR¹²;

R¹² is hydrogen, (C₁-C₆)-alkyl or (C₆-C₁₂)-aryl; or

R² and R³ together or R³ and R⁴ together or R⁴ and R⁵ together are

(C₁-C₃)-alkylene which can be substituted by 1 or 2 (C₁-C₃)-alkylradicals or optionally substituted (C₆-C₁₂)-aryl radicals;

X is N or O;

with the proviso that R² is not —C(O)OR⁶ when X is O;

and their physiologically tolerable salts.

Preferred compounds of the formula I are those in which the radicals R¹,R², R³, R⁴ and R⁵ do not each have the same meaning, and theirphysiologically tolerable salts.

Preferred compounds of the formula I are furthermore those in which onlythree of the radicals R¹, R², R³, R⁴, R⁵ have the same meaning, andtheir physiologically tolerable salts.

Particularly preferred compounds of the formula I are those in whichonly two of the radicals R¹, R², R³, R⁴, R⁵ have the same meaning, andtheir physiologically tolerable salts.

Very particularly preferred compounds of the formula I are those inwhich all radicals R¹, R², R³, R⁴, R⁵ have a different meaning, andtheir physiologically tolerable salts.

Preferred compounds of the formula I are those in which at least one ofthe radicals R¹, R², R³, R⁴, R⁵ is hydrogen, —C(O)NR⁶R⁷, (C₁-C₈)-alkyl,(C₀-C₆)-alkyl-(C₆-C₁₂)-aryl, preferably phenyl or benzyl; the arylmoiety of the (C₁-C₆)-alkyl-(C₆-C₁₂)-aryl radical being unsubstituted ormono-, di- or trisubstituted by (C₁-C₆)-alkyl, cyano, nitro, CF₃, Cl, Bror (C₁-C₄)alkoxy, preferably methoxy, and R⁶ and R⁷ independently of oneanother are hydrogen, (C₁-C₄)-alkyl, benzyl,(C₁-C₃)-alkylene-(C₃-C₇)-cycloalkyl, (C₁-C₃)-alkylene-CO—OR¹²,(C₁-C₃)-alkylene-(C₁-C₃)-alkoxy, phenyl, optionally substituted by oneor two radicals from the group consisting of CF₃, Cl, Br, F, nitro,cyano; and R¹² is as defined above;

or R³ and R⁴ together or R⁴ and R⁵ together are —CH₂— which issubstituted by 1 or 2 methyl radicals or optionally substituted phenylradicals, and the other radicals are as defined above,

and their physiologically tolerable salts.

Preferred compounds of the formula I are also those in which X is equalto —O— and the other radicals are as defined above, and theirphysiologically tolerable salts.

The invention furthermore relates to compounds of the formula II

in which:

R¹ is a linker group which can be linked via a covalent bond to acarrier functionalized by a heteroatom, for example N, O or Cl:

R², R³, R⁴, R⁵ independently of one another are a protective groupcustomary in sugar chemistry;

Y is O or S, preferably S;

X is O or N, preferably O.

Protective groups customary in sugar chemistry are, for example, thosesuch as are described, for example, in T. W. Greene, P. G. Wuts“Protective Groups in Organic Synthesis”, 2nd Edition, Wiley/New York,1991.

Suitable protective groups for compounds of the formula II are, forexample, silyl protective groups, e.g. TBDPS; alkoxyalkyl groups, e.g.ethoxyethyl; allyl groups; acyl groups such as acetyl or benzoyl;acetals and ketals such as isopropylidene or optionally substitutedbenzylidene.

Preferred compounds of the formula II are those in which the radicalsR², R³, R⁴ and R⁵ are not all the same protective group.

Preferred compounds of the formula II are furthermore those in whichonly two of the radicals R², R³, R⁴, R⁵ are an identical protectivegroup.

Very particularly preferred compounds of the formula II are those inwhich the radicals R², R³, R⁴, R⁵ are each a different protective group.

Preferred compounds of the formula II are also those which have anorthogonal protective group pattern with protective groups from thefollowing different classes:

base-labile protective groups, such as the acetate or benzoyl group;

acid-labile protective groups, such as acetal- or ketal-like protectivegroups such as the ethoxyethyl group;

fluoride-labile protective groups, such as the tert-butyidimethylsilylor tert-butyidiphenylsilyl group;

a protective group removable by transition metal catalysis, such as theallyl group;

sulfur-containing protective groups, such as in the linker system.

The invention also relates to compounds of the formula II, in which:

R⁵ is a linker group which can be linked via a covalent bond to acarrier functionalized by a heteroatom, for example N, O or Cl;

R¹, R², R³, R⁴ independently of one another are a protective groupcustomary in sugar chemistry;

Y is S or O, preferably S;

X is O or N, preferably O.

The invention also relates to compounds of the formulae IIa, IIb and IIc

in which:

Y is S or O, preferably S;

X is O or N, preferably O;

R¹ is a linker group which can be linked via a covalent bond to acarrier functionalized by a heteroatom, for example N, O or Cl;

R² in the case in which X is equal to 0, is a base-labile protectivegroup such as, for example, acetyl or benzoyl;

in the case in which X is equal to N, is a base-labile protective groupsuch as, for example, a phthaloyl protective group, or DDE(1-(4,4-dimethyl-2,6-dioxocyclohexylidene-ethyl) or NDE(2-acetyl4-nitroindan-1,3-dione);

R³ is an allyl protective group;

R⁴ is an acid-labile protective group, such as acetal- or ketal-likeprotective groups, for example ethoxyethyl or SEM(2-(trimethylsilyl)ethoxymethyl);

R⁵ is a suitable silyl protective group, such as, for example,tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

In general, suitable silyl protective groups for R⁵ are fluoride-labileprotective groups, which are more stable, i.e. more difficult to remove,than a trimethylsilyl radical.

The invention also relates to compounds of the formula IIa, in which R⁴and R⁵ together are an acetal- or ketal-like protective group such as,for example, isopropylidene or benzylidene and the other radicals X, Y,R¹, R² and R³ are as defined above.

The invention additionally relates to compounds of the formula IIb, inwhich R³ and R⁴ together are an acetal- or ketal-like protective groupsuch as, for example, isopropylidene or benzylidene and the otherradicals X, Y, R¹, R² and R⁵ are as defined above.

A suitable linker group R¹ or R⁵ is, for example, a group of the formulaIII

(C₁-C₆)-alkylene-[N—C(O)]_(n)—[(C₆-C₁₂)-arylene]_(p)—(C₀-C₆)-alkylene-C(O)R₉  (III)

in which n and p are 0 or 1, where p and n cannot simultaneously be 1;

R⁹ is OR¹⁰ or NR¹¹R¹¹, where

R¹⁰ is H, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-(C₆-C₁₂)-aryl, and

R¹¹ independently of one another is H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-(C₆-C₁₂)-aryl or a polymeric solid support.

Preferred compounds of the formula I or II are also those in which R²and R³ together, or R³ and R⁴ together or R⁴ and R⁵ together form abenzylidene radical or isopropylidene radical and the other radicals areas defined above.

Preferred compounds of the formula I and formula II are furthermorethose in which the monosaccharide structure is a glucose unit, agalactose unit or a mannose unit.

The compounds of the formula II and of the formula IIa, IIb or IIc arevaluable intermediates for the preparation of compounds of the formulaI.

(C₁-C₆)-Aryl is understood, for example, as meaning phenyl, naphthyl orbiphenyl.

Alkyl, alkenyl, alkynyl, alkylene and radicals derived therefrom suchas, for example, alkoxy can be straight-chain or branched, thosebranched radicals being preferred in which the branching site is notdirectly situated on the linkage site to the monosaccharide structure.

Halogen is preferably fluorine, chlorine or bromine.

A heteroaryl radical within the meaning of the present invention is theradical of a monocyclic or bicyclic (C₃-C₉)-heteroaromatic whichcontains one or two N atoms and/or an S or an O atom in the ring system.For the term “heteroaromatic”, see Garrat, Vollhardt, Aromatizität[Aromaticity], Stuttgart 1973, pages 131-153. Examples of suitableheteroaryl radicals are the radicals of thiophene, furan,benzo[b]thiophene, benzofuran, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, quinoline, isoquinoline,oxazole, isoxazole, thiazole, isothiazole, isobenzofuran, indolizine,isoindole, indazole, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline and furazan.

As indicated above, aryl, alkyl, heteroaryl and radicals derivedtherefrom can be monosubstituted or, if chemically possible,alternatively polysubstituted.

Suitable polymeric solid supports are, for example, crosslinkedpolystyrenes (e.g. aminomethylpolystyrene (AMPS) or Tentagel.

If not stated otherwise, chiral centers can be present in the R or inthe S configuration. The invention relates both to the optically purecompounds and to mixtures of stereoisomers such as mixtures ofenantiomers and mixtures of diastereomers.

Suitable salts are, in particular, alkali metal and alkaline earth metalsalts, salts with physiologically tolerable amines and salts withinorganic or organic acids such as, for example, HCl, HBr, H₂SO₄, maleicacid, fumaric acid.

The abovementioned compounds of the formulae I and II and IIa, IIb orIIc respectively are derivatives of tetrahydropyran which can besynthesized rapidly and in automated form in good yields and highpurities on a solid phase with the aid of the combinatorial methoddescribed here.

Compounds of the formula I can be prepared, for example, with the aid ofintermediates of the formula II which have an orthogonal protectivegroup pattern with one or preferably a number of protective groups fromthe following different classes:

base-labile protective groups, such as the acetate or benzoyl group;

acid-labile protective groups, such as acetal- or ketal-like protectivegroups such as the ethoxyethyl group;

fluoride-labile protective groups, such as the tert-butyldimethylsilylor tert-butyldiphenylsilyl group;

a protective group which can be removed by transition metal catalysis,such as the allyl group;

sulfur-containing protective groups, such as in the linker system.

The invention thus relates to a process for the preparation of compoundsof the formula I

and their physiologically tolerable salts, in which:

R¹, R², R³, R⁴, R⁵ independently of one another are

1. hydrogen;

2. (C₁-C₁₂)-alkyl;

3. (C₂-C₈)-alkenyl;

4. (C₂-C₈)-alkynyl;

5. (C₁-C₆)-alkylene-(C₃-C₁₀)-cycloalkyl;

6. (C₀-C₆)-alkylene-(C₆-C₁₂)-aryl; preferably phenyl or benzyl;

7. (C₁-C₆)-alkoxy;

8. (C₀-C₆)-alkylene-CO—R⁸;

9. (C₁-C₆)-alkylene-(C₁-C₉)-heteroaryl;

10. carbamoyl;

11. —C(O)NR⁶R⁷;

12. —C(O)OR⁶;

13. a radical defined as in 2.-12., which is mono-, di- orpolysubstituted in the alkyl moiety and/or aryl or heteroaryl moiety bya radical from the group consisting of (C₁-C₆)-alkyl, NO₂, CN, halogen,CF₃ or (C₁-C₆)-alkoxy;

14. a radical defined as in 6. and 9., which is substituted in the arylor heteroaryl moiety by one, two or more halogen atoms; or

R² and R³ together or R³ and R⁴ together or R⁴ and R⁵ together are(C₁-C₃)-alkylene which can be substituted by 1 or 2 (C₁-C₃)-alkylradicals or optionally substituted (C₆-C₁₂)-aryl radicals;

R⁶ and R⁷ independently of one another are:

1. hydrogen;

2. (C₁-C₁₂)-alkyl;

3. (C₂-C₈)-alkenyl;

4. (C₂-C₈)-alkynyl;

5. (C₁-C₆)-alkylene-(C₃-C₁₀)-cycloalkyl;

6. (C₁-C₆)-alkylene-(C₆-C₁₂)-aryl; preferably benzyl;

7. (C₂-C₆)-alkyloxy;

8. (C₀-C₆)-alkylene-CO—R⁸;

9. (C₁ -C₆)-alkylene-(C₁-C₉)-heteroaryl;

10. (C₀-C₆)-alkylene-(C₁-C₆)-alkoxy;

11. (C₃-C₁₀)-cycloalkyl;

12. (C₆-C₁₂)-aryl, preferably phenyl;

R⁸ is hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₂)-aryl or OR¹²;

R¹² is hydrogen, (C₁-C₆)-alkyl or (C₆-C₁₂)-aryl; and

X is N or O; by

a) introduction of a suitable, preferably sulfur-containing linker onthe anomeric center of an unprotected, partially orthogonally protectedor completely orthogonally protected monosaccharide derivative of theformula

 in which R in each case independently of one another is hydrogen or aprotective group customary in sugar chemistry; and X is O or N,preferably O;

b) reaction of a compound linker-bonded in this way, to give compoundsof the formula II

 in which R¹ is a linker group which can be linked via a covalent bondto a support functionalized by a heteroatom, for example N, O or Cl, and

R², R³, R⁴, R⁵ independently of one another are a protective groupcustomary in sugar chemistry, Y is O or S, preferably S and X is O or N,preferably O, by successive or simultaneous introduction of protectivegroups onto the functional groups —OR or —X—R, the protective groupsbelonging to identical or different, preferably different, orthogonalprotective group classes;

c) linkage of the monosaccharide derivative of the formula II protectedin this way to a polymeric solid support via the linker;

d) selective deprotection of the functional group to be derivatized onthe polymeric solid support;

e) derivatization of the deprotected functional groups on the polymericsolid support, where the deprotection and subsequent derivatization ofthe different functional groups can be carried out selectively and alsoa number of equally protected functional groups can be deprotected andderivatized simultaneously;

f) removal of the derivatives bonded to the polymeric solid support, forexample by activation of the sulfur on the anomeric center by bromine,and subsequent conversion of the compound activated in this way into acompound of the formula I derivatized on the anomeric center.

For the synthesis of the selectively protected monosaccharidederivatives according to formula II or IIa, IIb or IIc respectively on asolid phase, linkage to the anomeric center via a thioglycoside or anO-glycoside, in particular via a thioglycoside, is suitable. In thiscase, the different monosaccharides such as, for example, glucose,galactose or mannose, differ only slightly in the design of theprotective groups and the sequence of their introduction. Thedifferences in the reactivity of the functional groups and thedifferences associated therewith in the sequence of introduction of thedifferent protective groups is a known problem in carbohydratechemistry.

The synthesis strategy for the preparation of compounds of the formulaeI and II is illustrated in scheme 1 by the example of the glucosederivative and is also transferable to other monosaccharides such as,for example, galactose (see scheme 3) or mannose (see scheme 4) with theabovementioned slight variations.

Compounds of the formula I can also be prepared by carrying out thelinkage of selectively protected compounds of the formula II to apolymeric solid support by means of another OH position, for example the6 OH position, such as shown in scheme 6 by the example of galactose.The linkage of the linker via the 6-OH position is possible, forexample, according to the synthesis route shown in scheme 5.

Bonding of a Glycosaccharide to the Support Material (Scheme 1)

Reaction of the known 3-0-allyl-protected glucose P-acetate 3 (K. Takeoet al., Carbohydrate Research 133, 1984, 275) with the succinimidelinker 2 prepared from 1 leads to compound 4. The β-configuredthioglycoside 7 can be prepared analogously from the N-acylatedcysteamine 6 by reaction with 3 under BF₃ catalysis. The deacetylationof 4 and 7 affords 8 homogeneously. Silylation on the C-6 hydroxyl group9 and introduction of the ethoxyethyl protective group affords 10.Hydrolysis of the imide structure in 10 and coupling of the resultingacid 11 to a suitable support such as, for example,aminomethylpolystyrene affords the resin 12 loaded with the protectedmonosaccharide.

Reaction on the Solid Phase (see Scheme 2)

The removal and reaction of the protected monosaccharide 12 on the solidphase to give compounds of the formula I (13) is shown by way of examplein scheme 2. The C-2 hydroxyl function is deacetylated by reaction withhydrazine, the hydroxyl function can then be activated by reaction withpotassium tert-butoxide or phosphazene as a base (R. Schwesinger, H.Schlemper, Angew. Chem. 99, 1987, 1212-1214). The activated derivativeis trapped by means of electrophiles. An analogous reaction can becarried out in the case of a C-2 amino function. The protective groupused here is, for example, the Fmoc group, which can be removed bypiperidine.

The removal of the allyl ether on the C-3 hydroxyl group is carried outunder zirconocene catalysis (E. Negishi, Tetrahedron Lett. 1986, 27,2829-2832; E. Negishi, Synthesis, 1988, 1-19). The functionalization iscarried out analogously to the manner described above. By this means,the use of strong acids, such as would be necessary in other removalmethods familiar to the person skilled in the art, can be avoided andthe orthogonality to the other protective groups is guaranteed.

Alternatively to the base-catalyzed functionalization, the allyl etherprotective group can be converted into a propyl group by reduction withdiimine (see Hüning, H. R. Müller, W. Thier, Angew. Chem. 1965, 77,368-377). The C₄ hydroxyl function can be removed by transacetalizationin an analogous manner to that used in the case of THP acetals (cf. E.J. Corey, H. Niwa, J. Knolle, J. Am. Chem. Soc. 1978, 100, 1942-1943).The functionalization is carried out as described above. The C-6hydroxyl function is desilylated by reaction with fluoride ions; thereaction with electrophiles is carried out analogously to C-2.

The individual steps can be carried out in a different sequence onaccount of the compatibilities.

After completion of the functionalization of the various groups, theanomeric position is activated by reaction of the polymerically bondedselectively protected monosaccharide with bromine/di-tert-butylpyridine.The 1-bromo derivative is converted into a derivative functionalized onthe anomeric center by reaction with alcohol.

Synthesis Sequence for the Preparation of Galactose Derivatives (seeScheme 3)

Starting from galactose pentaacetate 14, the thioglycoside 16 isprepared by boron fluoride-catalyzed reaction with 15. Reaction withsodium methoxide affords 17 with deacetylation. The selective silylationof 17 takes place on the C-6 hydroxyl function. The silyl ether 18 isconverted into the isopropylidene-protected derivative 19 usingdimethoxypropane. Acetylation by reaction with acetic anhydride affords20. After removal of the isopropylidene protective group, the dihydroxycompound is converted into the allyl ether derivative protected on C-4using dibutyltin oxide and allyl bromide. Introduction of theethoxyethyl protective group affords 21. The ester is hydrolyzed withlithium hydroxide analogously to glucose.

Synthesis Sequence for the Preparation of Mannose Derivatives (seeScheme 4)

Mannose pentaacetate 22 is reacted with thiol 6 with boron trifluoridecatalysis to give the thiomannoside 23. Removal of the acetateprotective groups by sodium methoxide affords 24. Reaction withdimethoxybenzaldehyde affords the acetal 25. Reaction with dibutyltinoxide and allyl bromide leads to the 3-O-allyl ester. By acetylationwith acetic anhydride, 26 is prepared. The removal of the ketal andsubsequent selective silylation on C-6 affords a silyl ether.Introduction of the ethoxyethyl protective group affords 27. The esterin 27 is hydrolyzed with lithium hydroxide analogously to glucose.

Bonding to a Polymeric Solid Support via the 6-OH Position (Scheme 5)

For anchorage via the primary hydroxyl group, a thioglycoside 28, forexample, can be used as a starting material. The removal of the TBDPSgroup is carried out with tetrabutylammonium fluoride in THF. For theintroduction of the linker, for example, etherification according toMitsunobu is possible. The protection of the 4-hydroxyl group in 30 iscarried out with slight warming with SEM-CI and Hujnig's base indichloromethane.

Synthesis Sequence for the Preparation of Galactose Derivatives Whichare Bonded to a Polymeric Solid Support via the 1-OH Group (Scheme 6)

After binding of the glycoside to the solid polymeric support, the 1-OHgroup and the 2-OH group are first to be functionalized in the desiredsequence, then the SEM group and the allyl ether are removedsuccessively and the 3- and 4-positions are derivatized. The detachmentof the solid polymer, for example using cerium ammonium nitrate (CAN),and the functionalization of the 6-OH function are then carried out.

Coupling of a methyl galactosylmercaptobutyrate to anamino-funtionalized polymeric support via the 1-position (scheme 7)

On account of their polyvalency and their defined spatial arrangement,the compounds of the formulae II, IIa, IIb and IIc are suitable asstructural units for biological mimetics, for example peptide mimetics,and are a useful aid for the preparation and/or discovery of new leadstructures and the identification of potential active compounds.

The compounds of the formula I prepared with the aid of the compounds ofthe formula II, IIa, IIb or IIc have potential diagnostic and/orpharmacological action in various forms of disorder. Autoimmune diseasesand carcinomatous disorders, for example, may be mentioned.

On account of their potentially valuable pharmacological properties, thecompounds according to the present invention and their physiologicallytolerable salts are very highly suitable for use as therapeutics inmammals, in particular man.

The present invention therefore furthermore relates to a pharmaceuticalcomprising one or more compounds of the formula I and/or itspharmacologically tolerable salts, and their use for the production of apharmaceutical for the therapy or prophylaxis of autoimmune diseases,for example rheumatism or carcinomatous disorders.

The pharmaceuticals are particularly suitable for the treatment of acuteand chronic inflammation, which can be characterizedpathophysiologically by a disorder of the cell circulation, for exampleof lymphocytes, monocytes and neutrophilic granulocytes. These includeautoimmune disorders such as acute polyarthritis, rheumatoid arthritisand insulin-dependent diabetes (diabetes mellitus IDDM), acute andchronic transplant rejection, shock lung (ARDS, adult respiratorydistress syndrome), inflammatory and allergic skin disorders such as,for example, psoriasis and contact eczema, cardiovascular disorders suchas myocardial infarct, reperfusion injuries after thrombolysis,angioplasty or by-pass operations, septic shock and systemic shock. Afurther potential indication is the treatment of metastasizing tumors.Moreover, these pharmaceuticals, which are stable in the acid medium ofthe stomach, can be employed for the antiadhesive therapy ofHelicobacter pylori and related microorganisms, if appropriate also incombination with antibiotics. Therapy of the cerebral form of malaria isfurthermore conceivable with the aid of these pharmaceuticals.

Further potential application possibilities of the pharmaceuticals arein the treatment of metabolic disorders, such as diabetes andarteriosclerosis, of disorders of the cardiovascular and the centralnervous system and of disorders of bone metabolism, and in their use asan antiinfective or as a pharmaceutical having immunomodulatingproperties.

Pharmaceuticals which contain a compound of the formula I can beadministered here orally, parenterally, intravenously, rectally or byinhalation, the preferred administration being dependent on theparticular course of the disorder. The compounds I can be administeredhere on their own or together with pharmaceutical excipients, to bespecific both in veterinary and in human medicine.

The person skilled in the art is familiar on the basis of his expertknowledge with the auxiliaries which are suitable for the desiredpharmaceutical formulation. In addition to solvents, gel-forming agents,suppository bases, tablet auxiliaries, and other active compoundcarriers, it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizersor colorants.

For an oral administration form, the active compounds are mixed with theadditives suitable therefor, such as vehicles, stabilizers or inertdiluents, and brought into the suitable administration forms, such astablets, coated tablets, hard gelatin capsules, aqueous, alcoholic oroily solutions, by the customary methods. Inert carriers which can beused are, for example, gum arabic, magnesia, magnesium carbonate,potassium phosphate, lactose, glucose or starch, in particular cornstarch. In this case, preparation can take place both as dry and asmoist granules. Suitable oily vehicles or solvents are, for example,vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds, ifdesired with the substances customary therefor, such as solubilizers,emulsifiers or further excipients, are brought into solution, suspensionor emulsion. Suitable solvents are, for example: water, physiologicalsaline solution or alcohols, e.g. ethanol, propanol, glycerol, inaddition also sugar solutions such as glucose or mannitol solutions, oralternatively a mixture of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form ofaerosols or sprays are, for example, solutions, suspensions or emulsionsof the active compound of the formula I in a pharmaceutically acceptablesolvent, such as, in particular, ethanol or water, or a mixture of suchsolvents.

If required, the formulation can also additionally contain otherpharmaceutical excipients such as surfactants, emulsifiers andstabilizers and also a propellant. Such a preparation customarilycontains the active compound in a concentration of approximately 0.1 to10, in particular from approximately 0.3 to 3, % by weight.

The dose of the active compound of the formula I to be administered andthe frequency of administration depend on the potency and duration ofaction of the compounds used; in addition also on the nature andseverity of the disease to be treated and on the sex, age, weight andindividual responsiveness of the mammal to be treated.

The daily dose can be administered either by single administration inthe form of an individual dose unit or else of a number of small doseunits and also by multiple administration of subdivided doses atspecific intervals. The daily dose to be administered can moreover bedependent on the number of receptors expressed during the course of thedisease. It is conceivable that in the initial stage of the disease onlya few receptors are expressed on the cell surface and accordingly thedaily dose to be administered is lower than in severely ill patients.

On average, the daily dose of a compound of the formula I in a patientapproximately 75 kg in weight is at least 0.001 mg/kg, preferably atleast 0.01 mg/kg, to at most 10 mg/kg, preferably at most 1 mg/kg, ofbody weight.

Leukocyte Adhesion—Testing of the Activity of the Compounds According tothe Invention in vivo

In inflammatory processes and other conditions activating cytokines,tissue destruction by immigrating or microcirculation-blockingleukocytes plays a crucial role. The phase which is first and crucialfor the further disease process is the activation of leukocytes withinthe blood stream, in particular in the pre- and postcapillary area. Inthis case, after the leukocytes have left the axial flow of the blood, afirst attachment of the leukocytes to the vascular inner wall, i.e. tothe vascular endothelium, occurs. All subsequent leukocyte effects, i.e.the active diffusion through the vascular wall and the subsequentorientated migration into the tissue, are secondary reactions (Harlan,J. M., Leukocyte-endothelial interaction, Blood 65, 513-525, 1985). Thisreceptor-mediated interaction of leukocytes and endothelial cells isregarded as an initial sign of the inflammatory process. In addition tothe adhesion molecules already physiologically expressed, under theaction of inflammatory mediators (leukotrienes, PAF) and cytokines(TNF-alpha, interieukines) the temporally graduated, massive expressionof adhesion molecules on the cells occurs. They are at present dividedinto three groups: 1. immunoglobulin gene superfamily, 2. integrins and3. selectins. While the adhesion between molecules of the Ig superfamilyand the protein-protein bonds proceeds, lectin-carbohydrate bonds areprominent in the cooperation between selectins (Springer, T. A.,Adhesion receptors of the immune system. Nature 346, 425-434, 1990;Huges, G., Cell adhesion molecules—the key to an universal panacea,Scrips Magazine 6, 30-33, 1993; Springer, T. A., Traffic signals forlymphocyte recirculation and leukocyte emigration; The multistepparadigm, Cell 76, 301-314, 1994).

The Activity of the Compounds According to the Invention in vivo can beTested According to the Following Method:

The induced adhesion of leukocytes is quantified in the mesenterium ofthe rat using an intravital microscopic investigation technique(Atherton A. and Born G. V. R., Quantitative investigations of theadhesiveness of circulating polymorphonuclear leukocytes to blood vesselwalls. J. Physiol. 222, 447-474, 1972; Seiffge, D. Methoden zurUntersuchung der Rezeptor-vermittelten Interaktion zwischen Leukozytenund Endothelzellen im Entzündungsgeschehen [Methods for theinvestigation of receptor-mediated interaction between leukocytes andendothelial cells in the inflammation process], in: Ersatz- undErgätnzungsmethoden . zu Tierversuchen in der biomedizinischen Forschung[Replacement and supplementary methods for animal experiments inbiomedical research], Schöffl, H. et al., (Ed.) Springer, 1995 (inpress)). Under inhalation ether anesthesia, prolonged anesthesia isinitiated by intramuscular injection of urethane (1.25 mg/kg of BW).After exposure of vessels (femoral vein for the injection of substancesand carotid artery for blood pressure measurements), catheters are tiedinto these. The appropriate transparent tissue (mesenterium) is thenexposed by standard methods known in the literature and laid out on themicroscope stage and covered with a layer of paraffin oil at 37° C.(Menger, M. D. and Lehr, H., A. Scope and perspectives of intravitalmicroscopy-bridge over from in vitro to in vivo, Immunology Today 14,519-522, 1993). The test substance is administered i.v. to the animal(10 mg/kg). The experimental increase in blood cell adhesion is inducedby means of cytokine activation by systemic administration oflipopolysaccharide (LPS, 15 mg/kg) 15 minutes after administration oftest substance (Foster S. J., McCormick L. M., Ntolosi B. A. andCampbell D., Production of TNF-alpha by LPS-stimulated murine, rat andhuman blood and its pharmacological modulation, Agents and Actions 38,C77-C79, 1993, 18.01.1995). The increased adhesion of leukocytes to theendothelium caused thereby is quantified directly by vital microscopy orwith the aid of fluorescent dyes. All measuring processes are carriedout by video camera and stored on a video recorder. Over a period of 60minutes, the number of rolling leukocytes, (i.e. all visible rollingleukocytes, which are slower than the flowing erythrocytes) and thenumber of adhering leukocytes on the endothelium (residence time longerthan 5 seconds) are determined every 10 minutes. After completion of theexperiment, the anesthetized animals are put to sleep without excitationin a pain-free manner by systemic injection of T61. For evaluation, theresults of 8 treated animals in each case are compared (in percent) withthose of 8 untreated animals (control group).

EXAMPLES Example 1 N-(2-Thioethyl)succinimide 2

A solution of 24.2 g (0.21 mmol) of cysteamine hydrochloride 1 in 50 mlof H₂O is treated with 19.7 g (0.23 mol) of NaHCO₃ and stirred for 45min. It is then concentrated in vacuo and the residue is taken up in 100ml of acetic acid. After addition of 21.3 g (0.21 mol) of succinicanhydride, the suspension is heated under reflux for 3 h. Theprecipitate resulting on cooling of the solution is filtered off, washedwith cold acetic acid and the filtrate is freed from the solvent invacuo. The product is purified by chromatography on silica gel usingpetroleum ether/ethyl acetate (1:1).

Yield: 13.0 g (38%) of colorless, amorphous solid. R_(f)=0.71(EtOAc:HOAc=30:1 v/v), m.p.: 44-45° C. C₆H₉NO₂S (159.2) Calc.: C 45.26 H5.70 N 8.80 S 20.14; Found: C 45.16 H 5.76 N 8.71 S 20.20.

Example 2N-[2-S-(2′,4′,6′-Tri-O-acetyl-3′-O-allyl-D-glucopyranosyl)thioethyl]-succinimide4

4 ml (32 mmol) of boron trifluoride etherate in 10 ml of absol. CH₂Cl₂are added dropwise to a solution of 2.0 g (5.15 mmol) of the acetate 3and 980 mg (6.18 mmol) of N-(2-thioethyl)succinimide 2 in 55 ml ofabsol. CH₂Cl₂ cooled to 0° C. under argon. The ice cooling is thenremoved and the reaction is stirred further at room temp. After 16 h,the mixture is treated with 100 ml of CH₂Cl₂ and extracted twice withsatd NaHCO₃ solution. The organic phase is dried over MgSO₄ and thesolvent is removed in vacuo. The product is purified by chromatographyon silica gel using petroleum ether/ethyl acetate (2:1) and the productis then reprecipitated from ethyl acetate/n-pentane. Yield: 1.71 g (75%)of colorless, amorphous solid.

R_(f)=0.27 (PE:EtOAc=1:2 v/v), [α]_(D) ²=−41.8° (c 1.0, CHCl₃), m.p.:108° C.

C₂₁H₂₉NO₁₀S (487.5) Calc.: C 51.74 H 6.00 N 2.87 S 6.58 Found: C 51.64 H6.13 N 2.88 S 6.50

200 MHz ¹H-NMR (CDCl₃): [ppm]=5.80-5.61 (m 1H, CH₂═CH); 5.18-4.97(CH₂═CH, H-2′ & H4′); 4.38 (d, 1H, J_(2.1)=10.01 Hz, H-1′); 4.19-3.94(m, 4H, ═CH═CH₂, H-6a/b′); 3.79-3.50 (m, 4H, H-3′, H-5′ & NCH₂ Cya);2.93-2.79 (m, 1H, SCH₂ Cya); 2.76-2.61 (m, 1H, SCH₂ Cya); 2.65 (s, 4H,COCH₂ Suc); 2.03, 2.02 (2×s, 9H, CH₃ Ac). 100.6 MHz-¹³C-NMR (CDCl₃):[ppm]=176.6 (COCH₂); 169.1 (COCH₃); 134.2 (CH₂═CH); 116.8 (CH₂═CH);83.3, 81.0, 76.3, 73.0, 71.1, 69.4 (C-1′, C-2′, C-3′, C₄′, C-5′,═CH—CH₂); 62.3 (C-6′); 38.2 (CH₂CO Suc); 28.0 (NCH₂ Cya); 27.2 (SCH₂Cya); 20.8, 20.7, 20.6 (CH₃ Ac). The resulting α-anomer can be separatedby chromatography. Yield: 0.19 g (8%), colorless oil. R_(f)=0.33(PE:EtOAc=1.2 v/v).

Example 3 Monomethyl N-(2-Thioethyl)succinamidate 6

11.0 g (96.8 mmol) of cysteamine hydrochloride 1 are suspended in 75 mlof absol. acetonitrile under argon. 60 ml (345.0 mmol) of Hünig's baseare slowly added dropwise to this with ice-cooling in an argoncountercurrent.

After 5 min, 16.4 ml (130.0 mmol) of trimethylchlorosilane are added inone portion. The mixture is stirred at 0° C. for 10 min before asolution of 11.93 ml (96.8 mmol) of monomethyl succinyl chloride 5 in 20ml of absol. acetonitrile is added dropwise. After 30 min at 0° C. and 2h at room temp., the solution is poured into 200 ml of ice water and theproduct is extracted twice with 200 ml of ethyl acetate each time. Thecombined organic phases are washed with 30 ml of 1N HCl, 50 ml of satdNaHCO₃ solution and 50 ml of satd NaCl solution, dried over MgSO₄ andthe solvent is removed in vacuo. Yield: 13.1 g (71%), weakly yellowishoil.

R_(f)=0.54 (EtOAc), R_(f)=0.58 (EtOAc:HOAc=30:1 v/v) C₇H₁₃NO₃S (191.3)

Calc.: C 43.96 H 6.85 N 7.32 S 16.76 Found: C 43.97 H 6.78 N 7.65 S16.16

90 MHz-¹H-NMR (CDCl3): [ppm] =3.62 (s, 3H, OCH₃); 3.37 (q, Jgem =6.26Hz, CH₂N Cya); 2.80-2.17 (m, 6H, SCH₂, 2×CH₂CO).

Example 4 MonomethylN-[2-S-(2′,4′,6′-Tri-O-acetyl-3′-O-allyl-β-D-glucopyranosyl)-thioethyl]succinamidate7

6.0 g (15.5 mmol) of 3 are dissolved in 120 ml of absol. CH₂Cl₂. Afteraddition of 3.32 g (18.5 mmol) of the thiol, the solution is cooled to0° C. under argon. A solution of 17.5 ml (139 mmol) of boron trifluorideetherate in 20 ml of absol. CH₂Cl₂ is slowly added dropwise to thismixture. The ice-cooling is then removed and the mixture is stirred atroom temp. for 6 h. The reaction mixture is extracted twice with satdNaHCO₃ solution, the organic phase is separated off and dried overMgSO₄, and the solvent is removed in vacuo. After chromatography onsilica gel using petroleum ether/ethyl acetate/HOAc (60:30:1), 6.8 g(85%) of a colorless, amorphous solid are obtained.

R_(f)=0.44 (EtOAc), R_(f)=0.51 (toluene:EtOH=4:1 v/v), m.p.: 75-77° C.,[α]_(D) ²=−5.3° (c 1, CHCl₃). C₂₂H₃₃NO₁₁S (519.57)

Calc.: C 50.82 H 6.40 N 2.70 S 6.17 Found: C 50.74 H 6.44 N 2.76 S 6.23

200 MHz-¹H-NMR (CDCl₃): [ppm]=6.33 (t_(b), 1H, J_(gem)=5.13 Hz, NH);5.80-5.61 (m, 1H, CH₂═CH); 5.184.87 (m, 4H, CH₂═CH, H-2′ & H-4′); 4.38(d, 1H, J_(2.1)=9.76 Hz, H-1′); 4.114.00 (m, 2H, H-6′a/b); 3.62 (s, 3H,CO₂CH₃); 3.59-3.41 (m, 3H, H-3′, H4′, H-5′); 3.38-3.24 (m, 2H, CH₂NCya); 2.89-2.51 (m, 4H, SCH₂ Cya & CH₂CO₂ Suc); 2.43 (t, 2H,J_(gem)=6.41 Hz, CH₂CON Suc); 2.05, 2.02, 2.01 (3×s, 9H, CH₃ Ac).

Example 5 N-[2-S-(3′-O-Allyl-D-glucopyranosyl)thioethyl]succinimide 8

2.6 ml (2.6 mmol) of a 1M NaOMe solution in methanol are added underargon to 7.76 g (14.93 mmol) of thioglycoside 7 (crude product)dissolved in 60 ml of methanol p.a. The reaction solution is stirred at50° C. for 12 h, neutralized (5 min) with acidic ion exchangerAmberlyst® 15, and the ionic exchanger is removed by filtration andwashed with methanol. The filtrate is freed from the solvent in vacuo.After chromatography on silica gel using toluene/EtOH (4:1), 4.86 g(86%) of a colorless oil are obtained, which solidifies after some timeto give a colorless, amorphous solid.

R_(f)=0.27 (toluene:EtOH=4:1 vtv), m.p.: 98-99° C., [α]_(D) ²=−37.2° (c1.0, CHCl₃). CH₁₅H₂₃NO₇S (361.4)

Calc.: C 49.85 H 6.41 N 3.88 S 8.87 Found: C 49.89 H 6.62 N 3.86 S 8.83

400 MHz ¹H-NMR (CDCl₃): [ppm]=5.98-5.88 (m, 1H, CH₂═CH); 5.27 (d, 1H,J_(vic,trans)=17.32 Hz, CH₂═CH); 5.16 (d, 1H, J_(vic,cis)=10.27 Hz,CH₂═CH); 4.43 (dd, 1H, J_(gem)=12.62 Hz, J_(vic)=5.58 Hz, ═CH—CH₂); 4.32(d, 1H, J_(2.1)=9.69 Hz, H-1′); 4.26 (dd, 1H, J_(gem)=12.91 Hz,J_(vic)=5.87 Hz, ═CH—CH₂); 3.89-3.86 (m, 1H, H-6′a); 3.79-3.68 (m, 3H,H-2′, H4′ & H-6′b); 3.54 (t, 1H, J_(2.3)=J_(4.3)=9.25 Hz, H-3′);3.44-3.34 (m, 2H, CH₂N Cya); 3.29 (t, J_(3.4)=J_(5.4)=8.51 Hz, H-5′);3.09, 3.03 (2×s_(b), 2H, OH); 2.97-2.90 (m, 1H, SCH₂ Cya); 2.83-2.75 (m,1H, SCH₂ Cya); 2.71 (s, 4H, CH₂CO Suc).

Example 6N-[2-S-(2′-O-Acetyl-3′-O-allyl-D-glucopyranosyl)thioethyl]succinimide 8a

Variant 1: By Deacetylation of the Succinimide 4

1.15 g (2.36 mmol) of thioglycoside are cooled to 0° C. under argon in25 ml of methanol p.a. 13 mg (0.24 mmol) of NaOMe are added to theresulting suspension. After about 2 h, the precipitate dissolves andafter a further 45 min the reaction is ended by addition of acidic ionexchanger Amberlyst® 15. The mixture is filtered, the ion exchanger iswashed with methanol and the combined filtrates are freed from thesolvent in vacuo. After chromatography on silica gel using toluene/EtOH(4:1), 895 mg (94%) of a colorless, amorphous solid are obtained.

Variant 2: By Deacetylation of the Acyclic Derivative 7

A solution of 2.6 g (5.0 mmol) of the glycoside in 50 ml of methanolp.a. is treated with 27.0 mg (0.5 mmol) of NaOMe at −15° C. After 1 h,no conversion can be detected by thin-layer chromatography, so a further27 mg (0.5 mmol) of NaOMe are added and the temperature is increased to0° C. As the formation of a further, more polar product (deacetylationin the 2-position) can be detected in the thin-layer chromatogram, thereaction is terminated after 6 h by addition of acidic ion exchangerAmberlyst® 15. The solution is filtered, the ion exchanger is washedwith methanol and the solvent is removed from the combined filtrates invacuo. The product is purified by chromatography on silica gel usingtoluene/EtOH (4:1). Yield: 1.2 g (90%), colorless, amorphous solid.

C₁₇H₂₅NO₈S (403.5) Calc.: C 50.61 H 6.25 N 3.47 S 7.95 Found: C 49.85 H6.59 N 3.87 S 7.95

200 MHz-¹H-NMR (CDCl₃): [ppm]=5.92-5.73 (m, 1H, CH₂═CH); 5.24-5.08 (m,2H, CH₂═CH); 4.86 (t, 1H, J_(1.2)=J_(3.2)=9.52 Hz, H-2′); 4.37 (d, 1H,J_(2.1)=7.76 Hz, H-1′); 4.25-4.08 (m, 2H, ═CH—CH₂); 3.91-3.55 (m, 4H,H-3′, H-4′, H-6′a/b); 3.49-3.34 (m, 4H, H-5′, CH₂N Cya & OH); 2.99-2.71(m, 2H, SCH₂ Cya); 2.68 (s, 4H, CH₂CO Suc); 2.04 (s, 3H, CH₃ Ac).

Example 7N-[2-S-(2′-O-Acetyl-3′-O-allyl-6′-O-tert-butyldiphenylsilyl-D-glucopyranosyl)-thioethyl]succinimide9

1.0 g (2.48 mmol) of the succinimide 8a is dissolved in 20 ml of absol.CH₂Cl₂, treated with 583 mg (10.7 mmol) of imidazole, 0.74 ml (3.57mmol) of tert-butydiphenylchlorosilane and a spatula-tipful of DMAP andstirred at room temp. After 2 h, the mixture is diluted with 100 ml ofCH₂Cl₂ and extracted with 50 ml of 1N HCl and satd NaCl solution. Theorganic phase is dried over MgSO₄ and the solvent is removed in vacuo.After chromatography on silica gel using petroleum ether/ethyl acetate(1:1), 1.43 g (90%) of a colorless solid are obtained.

R_(f)=0.47 (PE:EtOAc=1:1 v/v), m.p.: 39-40° C.

C₃₃H₄₃NO₈SSi (641.9) Calc.: C 61.75 H 6.75 N 2.18 S 5.00 Found: C 61.58H 7.12 N 2.17 S 4.81

400MHz-¹H-NMR (CDCl₃): [ppm]=7.67-7.65 (m, 4H, PhSi); 7.42-7.33 (m, 6H,PhSi); 5.89-5.82 (m, 1H, CH₂═CH); 5.24 (dd, 1H, J_(vic,trans)=17.22 Hz,J_(gem)=1.58 Hz, CH₂═CH); 5.14 (d, 1H, J_(vic,cis)=10.41 Hz, CH₂═CH);4.91 (t, 1H, J1.2=J_(3.2)=9.56 Hz, H-2′); 4.42 (d, 1H, J_(2.1)=9.97 Hz,H-1′); 4.25-4.14 (m, 2H, ═CH—CH₂); 3.90 (d, 2H, J=4.51 Hz, H-6′a/b);3.76 (t, 1H, J_(3.4)=J_(5.4)=9.21 Hz, H-4′); 3.70-3.63 (m, 2H, H-3′ &H-5′); 3.47-3.41 (m, 2H, CH₂N Cya); 2.89 (s, 1H, OH); 2.87-2.81 (m, 1H,SCH₂ Cya); 2.75-2.62 (m, 1H, SCH₂ Cya); 2.61 (s, 4H, CH₂CO Suc);2.07 (s,3H, CH₃ Ac); 1.01 (s, 9H, CH₃ tBuSi).

Example 8N-[2-S-(2′-O-Acetyl-3′-O-allyl-6′-O-tert-butyldiphenylsilyl-4′-O-(1″-(R/S)-ethoxyethyl)-D-glucopyranosyl)thioethyl]succinimide 10

A solution of 1.26 g (1.96 mmol) of the succinimide 9 in 20 ml of absol.CH₂Cl₂ is treated with 0.94 ml (9.80 mmol) of ethyl vinyl ether and 246mg (0.98 mmol) of pyridinium toluene-4-sulfonate and stirred at roomtemp. After 3 h, the reaction solution is diluted with 50 ml of CH₂Cl₂and extracted twice with 30 ml of satd NaHCO₃ solution each time. Theorganic phase is dried over MgSO₄ and the solvent is removed in vacuo.

Yield: 1.37 g (98%), colorless oil. R_(f)=0.59 (PE:EtOAc=1:1 v/v),

C₃₇H₅₁NO₉SSi (714.0) Calc.: C 62.25 H 7.20 N 1.96 S 4.49 Found: C 61.61H 6.86 N 2.00 S 5.06 (crude product)

400MHz-¹H-NMR (CDCl₃): [ppm]=7.70-7.65 (m, 4H, PhSi); 7.40-7.33 (m, 6H,PhSi); 5.85-5.81 (m, 1H, CH₂═CH); 5.25-5.08 (m, 2H, CH₂═CH); 4.93-4.87(m, 1H, H-2′); 4.80 (q, 0.5H, J_(gem)=5.29 Hz, CHCH₃ EE); 4.65 (q, 0.5H,J_(gem)=5.28 Hz, CHCH₃ EE); 4.42 (d, 1H, J_(2.1)=9.68 Hz); 4.23 (dd, 1H,J_(gem)=12.62 Hz, J_(vic)=5.57 Hz, ═CH—CH₂); 4.16 (dd, 1H, J_(gem)=12.62Hz, J_(vic)=5.58 Hz, ═CH—CH₂); 3.90-3.86 (m, 2H, H-6′a/b); 3.75 (t, 1H,J_(3.4)=J_(5.4)=9.25 Hz, H4′); 3.68-3.58 (m, 3H, H-3′ & CH₂N Cya);3.52-3.41 (m, 3H, H-5′ & CH₃CH₂O EE); 2.86-2.81 (m, 1 Hz, SCH₂ Cya);2.74 (m, 1H, SCH₂ Cya); 2.60 (s, 4H, CH₂CO Suc); 2.06 (s, 3H, CH₃ Ac);1.28-1.11 (m, 4.5H, CHCH₃ & CH₃CH₂O EE); 1.00 (s, 9H, CH₃ tBuSi); 0.89(t, 1.5H, J=6.90 Hz, CH₃CH₂O EE).

Example 9N-[2-S-(2′-O-Acetyl-3′-O-ally-6′-O-tert-butyldiphenylsilyl-D-glucopyranosyl)thioethyl]-N⁴-benzylsuccinamide

2.8 g (4.36 mmol) of the succinimide 9 are dissolved in 30 ml of THF andcooled to 0° C. After addition of 15 mg of LiOH (4.8 mmol) in 10 ml ofH₂O, the mixture is stirred at 0° C. for 1.5 h, then acidified to pH=2.5with 1N HCl and extracted twice with 50 ml of CH₂Cl₂ each time. Thecombined organic phases are dried over MgSO₄ and freed from the solventin vacuo.

The crude product thus obtained is treated in 30 ml of absol. CH₂Cl₂with 0.96 ml (8.72 mmol) of benzylamine, 767 mg (6.54 mmol) of:N-hydroxysuccinimide and 900 mg (4.36 mmol) ofN,N′-dicyclohexylcarbodiimide. After 16 h, the precipitated urea isfiltered off and washed with CH₂Cl₂. The combined filtrates areextracted with 50 ml of 1N HCl and 50 ml of satd NaHCO₃ solution. Theorganic phase is dried over MgSO₄ and the solvent is removed in vacuo.The product is purified by chromatography on silica gel using petroleumether/ethyl acetate mixtures.

Yield: 2.13 g (67%), colorless, amorphous solid. R_(f)=0.53 (EtOAc),R_(f)=0.33 (EtOAc:PE:HOAc=30:30:1 v/v), m.p. 46-47° C.,

C₄₀H₅₂N₂O₈SSi (735.0) Calc.: C 65.37 H 7.13 N 3.81 S 4.36 Found: C 63.68H 6.83 N 3.71 S 4.45

200 MHz-¹H-NMR (CDCl₃): [ppm]=7.77-7.64 (m, 4H, PhSi); 7.50-7.28 (m, 6H,PhSi); 7.25-7.13 (m, 5H, Ph amide); 6.52 (t, 1H, J_(gem)=5.37 Hz, NH);6.34 (t, 1H, J_(gem)=5.37 Hz, NH); 5.95-5.76 (m, 1H, CH₂═CH); 5.28-5.12(m, 2H, CH₂═CH); 4.90 (t, 1H, J_(1.2)=J_(3.2)=9.53 Hz, H-2′); 4.46-4.36(m, 3H, H-1′, CH₂—Ph amide); 4.28-4.04 (m, 2H, ═CH—-CH₂); 3.91-3.89 (m,2H, H-6′a/b); 3.69 (t, 1H, J_(3.4)=J_(5.4)=9.28 Hz, H4′); 3.52-3.26 (m,5H, H-3′, H-5′, CH₂N Cya); 2.94 (s, 1H, OH); 2.85-2.58 (m, 2H, SCH₂Cya); 2.47-2.34 (m, 4H, CH₂CO Suc); 2.08 (s, 3H, CH₃ Ac); 1.03 (s, 9H,CH₃ tBuSi).

Preparation of the Galactose Unit Example 10 Methyl4-S-(2′,3′,4′,6′-tetra-O′-acetyl-β-D-galactopyranosyl)mercaptobutyrate16

A solution of 12 g (30 mmol) of 1,2,3,4,6-penta-O-acetylgalactose 14 and5.5 g of methyl mercaptobutyrate 15 in 150 ml of abs. dichloromethane isprestirred for 1 h with 10 g of thoroughly heated molecular sieve 4Å.The mixture is then cooled to 0° C. and 30 ml of boron trifluoride ethyletherate in 30 ml of abs. dichloromethane are added dropwise to thereaction mixture. It is then allowed to come to room temp. After 24 h,the precipitate is filtered off with suction through Celite and theorganic phase is stirred three times with 300 ml of satd NaHCO₃ solutioneach time. It is then washed with 600 ml of water, dried over MgSO₄ andfreed from the solvent. The product is purified by chromatography onsilica gel (eluent petroleum ether/ethyl acetate 2:1, column 20×8 cm).Yield 12.5 g (90%), yellow syrup, R_(f)=0.46 (petroleum ether/ethylacetate 1:1).

Example 11 Methyl4-S-(6-O′-tert-butyldiphenylsilyl-β-D-galactopyranosyl)mercaptobutyrate18

4.21 g (9.1 mmol) of 16 are dissolved in 40 ml of abs. methanol and0.098 g (1.82 mmol) of sodium methoxide is added. After 4 h, the mixtureis neutralized with acidic ion exchanger Amberlite® IR 120. The resin isfiltered off and washed with methanol. After the removal of the solventby distillation in vacuo and drying in a high vacuum, methylS-β-D-galactopyranosylmercaptobutyrate 17 is obtained quant. as acolorless solid, R_(f)=0.56 (chloroform/methanol 2:1). The crude productis dissolved in 20 ml of DMF and treated with 1.24 g (18.1 mmol) ofimidazole and 3.25 ml (12.7 mmol) of tert-butyldiphenylsilyl chloride.The mixture is stirred at room temp. for 5 h and the reaction is thenterminated by addition of 10 ml of water. After 10 min, the mixture isdiluted with 60 ml of dichloromethane and washed three times with 40 mlof water each time. The org. phase is dried over MgSO₄ and evaporatedafter filtration in vacuo. The residue is purified by chromatography onsilica gel. Yield 4.44 g (92%).

R_(f)=0.23 (petroleum ether/ethyl acetate 1:1), 0.63 (ethylacetate/acetic acid 30:1); 400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.98-7.64,7.40-7.36 (m, 10H, SiPh₂), 4.25 (d, 1H, J_(1.2)=9.6 Hz, 1-H), 4.10 (s,1H, 4-H), 3.88 (dd, 1H, J_(gem)=10.4 Hz, J_(6a.5)=6.3 Hz, 6-Ha), 3.84(dd, 1H, J_(gem)=10.9 Hz, J_(6b.5)=5.3 Hz, 6-H_(b)), 3.69 (dd, 1H,J_(2.1)=9.4 Hz, J_(2.3)=9.2 Hz, 2-H), 3.59 (s, 3H, COOCH₃), 3.56 (d, 1H,J_(3.4)=3.1 Hz, 3-H), 3.52 (dd, 1H, J_(5.6a)=5.7 Hz, J_(5.6b)=5.0 Hz,5-H), 3.06 (s_(br), 3H, OH), 2.72 (dt, 1H, J_(gem)=13.9 Hz, J_(vic)=7.0Hz, SCH_(a)), 2.66 (dt, 1 H, J_(gem)=13.9 Hz, J_(vic)=7.0 Hz, SCH_(b)),2.40-2.36 (m_(c), 2H, CH₂COOMe), 1.95-1.89 (m_(c), 2H, SCH₂CH₂), 1.02(s, 9H, SiC(CH₃)₃). 100.6 MHz-¹³C-NMR (CDCl₃): δ [ppm]=173.5 (COOMe),135.6; 135.5; 133.1; 133.0; 129.9; 127.8 (SiPh₂), 86.0; 78.4; 75.0;70.5; 69.1; 63.2 (C-1-C-6), 51.5 (COOCH₃), 32.7 (SCH₂), 29.2 (CH₂COOMe),26.8 (SiC(CH₃)₃), 25.3 (SCH₂CH₂), 19.1 (SiC(CH₃)₃).

Example 12 Methyl4-S-(6-O′-tert-butyldiphenylsilyl-3,4-O′-isopropylidene-β-D-galactopyranosyl)mercaptopropionate19

4.15 g (7.78 mmol) of 18 are dissolved in 35 ml of acetone dimethylacetal and the mixture is stirred at room temp. for 4 h after additionof 28 mg of p-TsOH. It is then neutralized with triethylamine. Thesolution is concentrated in vacuo and the oily residue is freed fromimpurities by chromatography on silica gel (eluent petroleum ether/ethylacetate 2:1, column 20×5 cm).

Yield 4.03 g (90%), colorless oil, R_(f)=0.54 1:1 (petroleum ether/ethylacetate 1:1).

400MHz-¹H-NMR (CDCl₃): δ [ppm]=7.70-7.66, 7.44-7.33 (m, 10H, Ph-H), 4.31(dd, 1H, J_(4.3)=5.3 Hz, J_(4.5)=1.3 Hz, 4-H), 4.21 (d, 1H, J_(1.2)=10.3Hz, 1-H), 4.04 (dd, 1H, J_(3.2)=7.0 Hz, J_(3.4)=5.6 Hz, 3-H), 3.90 (dd,1H, J_(gem)=10.8 Hz, J_(6a.5)=1.2 Hz, 6-H_(a)), 3.88 (dd, 1H,J_(gem)=10.8 Hz, J_(6b.5)=4.8 Hz, 6-H_(b)), 3.87-3.85 (m, 1H, 5-H), 3.60(s, 3H, COOCH₃), 3.52 (dd, J_(2.1)=8.8 Hz, J_(2.3)=8.5 Hz, 2-H), 2.75(dt, 1H, J_(gem)=13.2 Hz, J_(vic)=7.0 Hz, SCH_(a)), 2.35 (dt, 1H,J_(gem)=13.2 Hz, J_(vic)=7.0 Hz, SCH_(b)), 2.42-2.39 (m_(c), 2H,CH₂COOMe), 1.96-1.89 (m_(c), 2H, SCH₂CH₂), 1.50 (s, 3H, C(CH₃)₂), 1.34(s, 3H, C(CH₃)₂), 1.03 (s, 9H, C(CH₃)₃. 100.6 MHz-¹³C-NMR (CDCl₃): δ[ppm]=173.3 (COOMe), 135.6; 135.5; 129.7; 127.7; 127.6 (C-Ph), 110.0(C(CH₃)₃), 85.6; 79.1; 77.3; 73.3; 72.4; 62.7 (C-1-C-6), 51.5 (COOCH₃),32.5 (SCH₂), 29.4 (CH₂COOMe), 28.2 (C(CH₃)₂), 26.8 (C(CH₃)₃), 26.2(C(CH₃)₂), 25.2 (SCH₂CH₂).

Example 13 Methyl4-S-(2-O′-Acetyl-6-O′-tert-butyldiphenylsilyl-3,4-O′-isopropylidene-β-D-galactopyranosyl)mercaptobutyrate20

A solution of 27.6 g (48 mmol) of 19 in 100 ml of aceticanhydride/pyridine (1:1) is stirred for 5 h at room temp. It is thenconcentrated in a high vacuum and the residue is taken up in 100 ml ofdichloromethane. The solution is washed with 50 ml each of 0.5 N HCl,satd NaHCO₃ solution and water. After drying over MgSO₄, the mixture isfreed from the solvent in vacuo. Chromatography on silica gel (eluentpetroleum ether/ethyl acetate 4:1, column 30×10 cm) yields the titlecompound. Yield 24.3 g (82%), colorless oil,

R_(f)=0.66 (petroleum ether/ethyl acetate 1:1). 400 MHz-¹H-NMR (CDCl₃):δ [ppm]=7.70-7.66, 7.43-7.33 (m, 10H, Ph-H), 4.98 (dd, J_(2.1)=10.0 Hz,J_(2.3)=7.3 Hz, 2-H), 4.34 (d, 1H, J_(4.3)=5.3 Hz, 4-H), 4.31 (d, 1H,J_(1.2)=10.3 Hz, 1-H), 4.15 (dd, 1H, J_(3.2)=7.3 Hz, J_(3.4)=5.2 Hz,3-H), 4.10-3.86 (m, 3H, 6-H_(a,b), 5-H), 3.58 (s, 3H, COOCH₃), 2.72 (dt,1H, J_(gem)=12.9 Hz, J_(vic)=7.0 Hz, SCH_(a)), 2.60 (dt, 1H,J_(gem)=12.6 Hz, J_(vic)=7.0 Hz, SCH_(b)), 2.41-2.32 (m_(c), 2H,CH₂COOMe), 2.08 (s, 3H, COCH₃), 1.93-1.83 (m_(c), 2H, SCH₂CH₂), 1.53 (s,3H, C(CH₃)₂), 1.33 (s, 3H, C(CH₃)₂), 1.03 (s, 9H, C(CH₃)₃). 100.6MHz-¹³C-NMR (CDCl₃): δ [ppm]=173.2 (COOMe), 169.5 (COMe), 135.5; 135.5;133.4; 133.3; 129.7; 127.6; 127.6 (C-Ph), 110.2 (C(CH₃)₂), 82.7; 77.4;76.7; 73.4; 71.7; 62.6 (C-1- C-6), 51.4 (COOCH₃), 32.6 (SCH₂), 29.1(CH₂COOMe), 27.8 (C(CH₃)₂), 26.8 (C(CH₃)₃), 26.3 (C(CH₃)₂), 24.9(C(CH₃)₃), 20.9 (COCH₃), 19.2 (SCH₂CH₂).

Example 14 Methyl4-S-(3-O′-Allyl-2-O′-acetyl-4-O′-[1-(R/S)-ethoxyethyl]-6-O′-tert-butyidiphenyisilyl-β-D-galactopyranosyl)mercaptobutyrate21 a) Methyl4-S-(2-O′-Acetyl-6-O′-tert-butyidiphenyisilyl-β-D-galacto-pyranosyl)mercaptobutyrate

A solution of 23.97 g (38.86 mmol) of 20 in 370 ml of CHCl₃ is heated toreflux with 0.35 g (1.84 mmol) of p-toluenesulfonic acid and 22.70 ml(270 mmol) of ethanedithiol. After 5 h, the mixture is cooled to roomtemp. and washed with 50 ml each of satd sodium hydrogencarbonatesolution, 0.5 N HCl and water. The organic phase is dried over magnesiumsulfate. The product is obtained pure by chromatography on silica gel(eluent petroleum ether/ethyl acetate 1:1). Yield 16.66 g (74%),colorless oil, R_(f)=0.16 (petroleum ether/ethyl acetate 2:1). 400MHz-¹H-NMR (CDCl₃): δ [ppm]=7.68-7.63, 7.42-7.34 (m, 10H, Ph-H), 5.06(dd, J_(2.1)=9.6 Hz, J_(2.3)=9.6 Hz, 2-H), 4.31 (d, 1H, J_(1.2)=9.9 Hz,1-H), 4.11 (d, 1H, J_(4.3) =5.3 Hz, 4-H), 3.92-3.84 (m, 2H, 6-H_(a,b)),3.61 (d, 1H, J_(3.4)=3.4 Hz, 3-H), 3.58 (s, 3H, COOCH₃), 3.50 (t, 1H,J_(5.6)=5.5 Hz, 5-H), 2.73 (dt, 1H, J_(gem)=13.0 Hz, J_(vic)=7.2 Hz,SCH_(a)), 2.59 (dt, 1H, J_(gem)=13.0 Hz, J_(vic)=7.2 Hz, SCH_(b)),2.40-2.16 (m_(c), 2H, CH₂COOMe), 2.09 (s, 3H, COCH₃), 2.01-1.81 (m_(c),2H, SCH₂CH₂), 1.03 (s, 9H, C(CH₃)₃). 100.6 MHz-¹³C-NMR (CDCl₃): δ[ppm]=173.4 (COOMe), 170.8 (COMe), 135.5; 135.4; 132.9; 132.7; 129.9;127.8 (C-Ph), 83.2; 78.1; 73.7; 71.2; 69.6; 63.3 (C-1-C-6), 51.5(COOCH₃), 32.6 (SCH₂), 28.8 (CH₂COOMe), 26.8 (C(CH₃)₃), 25.1 (C(CH₃)₃),20.9 (COCH₃), 19.1 (SCH₂CH₂).

b) Methyl4-S-(3-O′-allyl-2-O′-acetyl-6-O′-tert-butyldiphenylsilyl-β-D-galactopyranosyl)mercaptobutyrate

A mixture of 5.7 g (9.8 mmol) of the compound from Ex. 14a) and 3.3 g(9.43 mmol) of dibutyltin oxide in 70 ml of benzene is heated to refluxfor 8 h in a water separator. 35 ml of benzene are then removed bydistillation and the mixture is treated with 1.76 g (9.43 mmol) oftetrabutylammonium bromide and 1.35 ml (15.6 mmol) of allyl bromide. Thesolution is stirred at 50° C. for 16 h. After addition of 5 ml ofmethanol, it is largely concentrated in vacuo. The residue is taken upin 50 ml of dichloromethane and washed three times with 10 ml of watereach time. After drying over MgSO₄, the solvent is removed in vacuo. Thecrude product is purified. by chromatography (eluent petroleumether/ethyl acetate 4:1, column 15×5 cm) on silica gel. Yield 3.79 g(63%) of yellowish oil, R_(f)=0.34 (petroleum ether/ethyl acetate 4:1).400MHz-¹H-NMR (CDCl₃): δ [ppm]=7.68-7.65, 7.42-7.34 (m, 10H, Ph-H),5.90-5.80 (m_(c), 1H, ═CH), 5.26 (d, 1H, J_(vic)=17.6 Hz, CH_(trans)═),5.20 (dd, 1H, J_(2.1)=10.0 Hz, J_(2.3)=9.8 Hz, 2-H, R+S), 5.18 (d, 1H,J_(vic)=11.8 Hz, CH_(cis)═), 4.30 (d, 1H, J_(1.2)=10.0 Hz, 1-H), 4.16(d, 1H, J_(4.5)=2.7 Hz, 4-H), 4.11 (dd, 1H, J_(gem)=12.9 Hz, J_(vic)=5.6Hz, ═CH—CH_(a)), 4.03 (dd, 1H, J_(gem)=12.9 Hz, J_(vic)=5.6 Hz,═CH—CH_(b)), 3.94 (dd, 1H, J_(gem)=10.3 Hz, J_(6a.5)=6.5 Hz, 6-H_(a)),3.86 (dd, 1H, J_(gem)=10.3 Hz, J_(6b.5)=5.6 Hz, 6-H_(b)), 3.59 (s, 3H,COOCH₃), 3.50 (dd, 1H, J_(5.6a)=J_(5.6b)=5.9 Hz, 5-H), 3.44 (dd, 1H,J_(3.2)=9.4 Hz, J_(3.4)=2.7 Hz, 3-H), 2.75 (dt, 1H, J_(gem)=13.2 Hz,J_(vic)=7.0 Hz, SCH_(a)), 2.61 (dt, 1H, J_(gem)=13.2 Hz, J_(vic)=7.0 Hz,SCH_(b)), 2.37 (m_(c), 2H, SCH₂CH₂), 2.07 (s, 3H, COCH₃), 1.88 (m_(c),2H, CH₂COOMe), 1.03 (s, 9H, SiC(CH₃)₃).

c) Methyl4-S-(3-O′-Allyl-2-O′-acetyl-4-O′-[1-(R/S)-ethoxyethyl]-6-O′-tert-butyldiphenylsilyl-β-D-galactopyranosyl)mercaptobutyrate

1.95 g (3.15 mmol) of the compound according to Example 14b) aredissolved in 45 ml of dichloromethane and the mixture is stirred at roomtemp. for 4 h after addition of 45 ml of ethyl vinyl ether and 0.39 g(1.56 mmol) of pyridium p-toluenesulfonate. The mixture is poured intosatd NaHCO₃ solution and the aq. phase is extracted with ethyl acetate.

The combined org. phases are then dried over MgSO₄, and freed from thesolvent in vacuo. Purification is carried out by chromatography onsilica gel (eluent petroleum ether/ethyl acetate 4:1, column 15×2 cm).Yield 1.49 g (69%), colorless oil,

R_(f)=0.39 (petroleum ether/ethyl acetate 4:1). 400 MHz-¹H-NMR (CDCl₃):δ [ppm]=8.03-8.01; 7.69-7.36 (m, 10H, Ph-H), 5.80-5.65 (²m_(c), 1H, ═CH,R+S), 5.56, 5.50 (2dd, 1H, J_(2.1)=J_(2.3)=9.8 Hz, 2-H, R+S), 5.26-5.01(m, 2H, CH_(trans)═, CH_(cis)═, R+S), 4.94 (q, 1H, CHCH₃), 4.52, 4.46(2d, 1H, J_(1.2)=10.3 Hz, 1-H, R+S), 4.16-3.45 (m, 7H, 4-H, ⁶-H_(a,b),5-H, 3-H, ═CH—CH_(a,b), R+S), 3.54, 3.53 (2s, 3H, COOCH₃, R+S),3.69-3.63, 3.32-3.25 (2m_(c), 2H, CH₂CH₃, R+S), 3.04-2.94, 2.89-2.78(2m_(c), 2H, SCH₂ R+S), 2.66, 2.60 (2t, J_(vic)=7.3 Hz, SCH₂CH₂, R+S),1.33, 1.26 (2d, 3H, J_(vic=)5.3 Hz, CHCH₃, R+S), 1.17, 0.95 (2t, 3H,J_(vic)=7.0 Hz, CH₂CH₃, R+S), 1.07, 1.05 (2s, 9H, C(CH₃)₃, R+S).

The hydrolysis of the ester is carried out as described in the case ofglucose.

Preparation of the Mannose Derivatives Example 15 MonomethylN-[2-S-(2′,3′,4′,6′-tetra-O-Acetyl-α-D-mannopyranosyl)thio-ethyl]succinamidate23

A solution of 11.1 g (34.3 mmol) of monomethylN-(2-thioethyl)succinamidate 6 and 43 ml (0.34 mol) of boron trifluorideetherate in 70 ml of CH₂Cl₂ is added dropwise with ice-cooling to 10.0 g(25.6 mmol) of the anomer mixture 22 in 300 ml of CH₂Cl₂. The solutionis warmed to room temp. and stirred for 12 h. The mixture is washedtwice with 500 ml of satd NaHCO₃ solution in each case and the organicphase is dried over MgSO₄. After chromatography on silica gel usingpetroleum ether/ethyl acetate (1:2), 5.5 g (44%) of pure α-product areobtained as a colorless oil and also 2.3 g (19%) of an α,β-mixedfraction as a yellowish oil.

R_(f)=0.24 (PE/EtOAc=1:2 v/v), R_(f)=0.52 (EtOAc/HOAc=30:1 v/v), 200MHz-¹H-NMR (CDCl₃): δ [ppm]=6.28 (s_(b), 1H, NH); 5.30-5.14 (m, 4H,H-1′, H-2′, H-3′ & H-4′); 4.37-4.06 (m, 3H, H-5′ & H-6′a/b); 3.65 (s,3H, CO₂CH₃); 3.57-3.39 (m, 2H, CH₂N Cya); 2.85-2.71 (m, 2H, SCH₂ Cya);2.63 (t, 2H, J_(vic)=7.08 Hz, CH₂CO Suc); 2.45 (t, 2H, J_(vic)=7.09 Hz,CH₂CON Suc); [lacuna].08, 20.7, 20.5 (3×s, 12H, CH₃ Ac).

Example 16 N-[2-S-(α-D-Mannopyranosyl)thioethyl]succinimide 24

1.5 ml of a 1 M solution of sodium methoxide in methanol are added underargon and with ice-cooling to 7.9 g (15.2 mmol) of the glycoside 23 in100 ml of methanol p.a., and the mixture is stirred at room temp. for 2h and neutralized with Amberlyst® 15. The ion exchanger is filtered off,washed with methanol and the solvent is removed in vacuo. Residues ofmethanol are removed by codistillation with toluene. 4.8 g (97%) areobtained as a yellowish oil, which still contains slight impurities. Thecrude product is employed in the next stage without furtherpurification.

R_(f)=(toluene:EtOH=4.1 v/v).

Example 17N-[2-S-(4′,6′-O-Benzylidene-α-D-mannopyranosyl)thioethyl]succinimide 25

5.5 g (10.55 mol) of the thiogiycoside 23 are treated at room temp. with100 mg (1.8 mmol) of NaOMe in 75 ml of methanol. After 2 h, thin-layerchromatographic checking indicates incomplete conversion, for whichreason a further 100 mg of NaOMe are added. After a further 1.5 h, themixture is neutralized with acidic ion exchanger Amberlyst® 15. The ionexchanger is filtered off and the solvent is removed in vacuo. The crudeproduct is treated in 50 ml of absol. DMF with 3.1 ml (20 mmol) ofbenzaldehyde dimethyl acetal and 112 mg (1 mmol) of p-toluenesulfonicacid and stirred at 50° C. and 50-70 mbar for 2 h. The mixture isneutralized with 10 ml of triethylamine and the solvent is removed in ahigh vacuum. The residue is taken up in 200 ml of CH₂Cl₂ and extractedtwice with 75 ml of NaHCO₃. The organic phase is separated off and driedover MgSO₄, and the solvent is removed in vacuo. By chromatography onsilica gel using petroleum ether/ethyl acetate mixtures, 3.33 g (77%) ofa colorless oil are obtained.

R_(f)=0.44 (EtOAc/HOAc=30:1 v/v), 200 MHz-¹H-NMR (CDCl₃): δ[ppm]=7.43-7.41 (m, 2H, Ph); 7.33-7.29 (m, 3H, Ph); 5.48 (s, 1H, PhCH);5.32 (s, 1H, H-1′); 4.19-3.43 (m, 8H, H-2′, H-3′, H4′, H-5′, H-6a/b′,NCH₂ Cya); 2.80-2.64 (m, 2H, SCH₂ Cya); 2.58 (s, 4H, COCH₂ Suc).

Example 18N-[2-S-(2′-O-Acetyl-3′-O-allyl-4′,6′-O-benzylidene-α-D-mannopyranosyly-thioethyl]succinimide26

330 mg (0.81 mmol) of 25 are treated with 227 mg (0.91 mmol) ofdibutyltin oxide in 20 ml of methanol. The suspension is heated underreflux for 2.5 h, freed from the solvent in vacuo and the residue isdried in a high vacuum. The tin acetal is treated with 0.12ml (1.4 mmol)of allyl bromide and 517 mg (1.4 mmol) of TBAI in 20 ml of absol.toluene and the mixture is stirred at 40° C. for 6 h. Thin-layerchromatographic checking indicates a low conversion. The reaction istherefore continued at 80° C. After 7 h, the solvent is removed in vacuoand the product is isolated by chromatography on silica gel two timesusing petroleum ether/ethyl acetate mixtures. 300 mg of a rust-coloredoil are obtained, which according to the NMR spectrum still contains tinresidues.

R_(f)=0.56 (toluene/EtOH=4:1 v/v), 200 MHz-¹H-NMR (CDCl₃): δ[ppm]=7.48-7.43 (m, 2H, Ph); 7.36-7.31 (m, 3H, Ph); 5.96-5.77 (m, 1H,CH₂═CH); 5.55 (s, 1H, PhCH); 5.40 (s, 1H, H-1); 5.26 (dd, 1H,Jgem,trans=17.09 Hz, J_(vic)=1.46 Hz, CH₂═CH); 5.16 (dd, 1H,J_(gem.cis)=10.26 Hz, J_(vic)=0.98 Hz, CH₂═CH); 4.31-4.01 (m, 5H, H-2,H6a/b, ═CH—CH₂); 3.88-3.60 (m, 3H, H-4, NCH₂ Cya); 3.29-3.20 (m, 2H,H-3, H-5); 2.85-2.76 (m, 2H, SCH₂ Cya); 2.69 (s, 4H, COCH₂ Suc).

300 mg (0.67 mmol) of 25 are stirred at room temp. for 1.5 h with 2 mlof acetic anhydride and a spatula-tipful [lacuna] in 10 ml of pyridine.The solvent is removed in vacuo and the product is purified bychromatography on silica gel using petroleum ether/ethyl acetate (1:1).191 mg (48% over two stages) of a yellow oil are obtained. R_(f)=0.63(toluene/EtOH=4:1 v/v), 1200 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.47-7.42 (m,2H, Ph); 7.37-7.32 (m, 3H, Ph); 5.96-5.70 (m, 1H, CH₂═CH); 5.66 (s, 1H,PhCH); 5.33-5.08 (m, 3H, CH₂═CH, H-2); 5.25 (s, 1H, H-1); 4.44-4.0 (m,5H, H4, H-6a/b, ═CH—CH₂); 3.85-3.45 (m, 4H, H-3, H-5, NCH₂ Cya);2.87-2.72 (m, 2H, SCH₂ Cya); 2.65 (s, 4H, COCH₂ Suc); 2.12 (s, 3H, CH₃Ac).

Example 19N-[2-S-(2′-O-Acetyl-3′-O-allyl-6′-O-tert-butyldiphenylsilyl-4′-O-(1″-(R/S)-ethoxyethyl)-α-D-mannopyranosyl)thioethyl]succinimide27

0.12 ml of a 48% strength solution of HBF₄ in water is added to 180 mg(0.37 mmol) of 26 in 10 ml of absol. acetonitrile and the reactionsolution is stirred for 2 h at room temp. Thin-layer chromatographicchecking shows complete conversion and the mixture is treated with 10 mlof satd NaHCO₃ solution and extracted twice with 50 ml of CH₂Cl₂. Thecombined organic phases are dried over MgSO₄ and the solvent is removedin vacuo. The residue is taken up in 10 ml of absol. CH₂Cl₂ and treatedwith 0.19 ml (0.72 mmol) of tert-butyldiphenylchlorosilane and 100 mg(1.5 mmol) of imidazole. After 16 h, the solution is diluted with 50 mlof CH₂Cl₂ and extracted with 0.5 N HCl solution. The organic phase isdried over MgSO₄ and the solvent is removed in vacuo. By chromatographyon silica gel using petroleum ether/ethyl acetate mixtures, 69 mg (30%)of the product are obtained as a colorless oil. R_(f)=0.21(toluene/EtOH=4:1 v/v), 400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.69-7.65 (m,4H, PhSi); 7.41-7.33 (m, 6H, PhSi); 5.89-5.80 (m, 1H, CH₂═CH); 5.32 (d,1H, J_(1.2)=1.17 Hz, H-2); 5.29 (s, 1H, H-1); 5.26 (dd, 1H,J_(vic,trans)=16.88 Hz, J_(gem)=1.62 Hz, CH₂CH); 5.18 (dd, 1H,J_(vic,cis)=11.74 Hz, J_(gem)=1.47 Hz, CH₂CH); 4.11 (dd, 1H,J_(gem)=12.32 Hz, J_(vic)=5.58 Hz, ═CH—CH₂); 4.00-3.88 (m, 5H, H-3, H4 &H-6a/b); 3.78-3.71 (m, 1H, H-5); 3.64-3.58 (m, 2H, CH₂N Cya); 2.82-2.68(m, 2H, SCH₂ Cya); 2.66 (s, 4H, CH₂CO Suc); 2.08 (s, 3H, CH₃ Ac); 1.03(s, (h, 9H, CH₃ tBuSi).

69 mg (0.11 mmol) of the succinimide are reacted with 0.1 ml (1.1 mmol)of ethyl vinyl ether and 27 mg (0.11 mmol) of pyridiniumtoluene-4-sulfonate in 10 ml of absol. CH₂Cl₂. After 4 h, the conversionaccording to the thin-layer chromatogram is only about 70%, so a further0.1 ml of ethyl vinyl ether and 27 mg of pyridinium toluene4-sulfonateare added and the reaction time is lengthened to 16 h. The mixture isdiluted with 30 ml of CH₂Cl₂ and extracted with satd NaHCO₃ solution.The organic phase is dried over MgSO₄ and the solvent is removed invacuo. By chromatography on silica gel using petroleum ether/ethylacetate (1:1) 42 mg (56%) of a colorless oil are obtained. In addition,some fractions are obtained which contain unreacted starting material.R_(f)=0.44 (toluene/EtOH=4:1 v/v), [α]=+96.1° (c 1, CHCl₃). 400MHz-¹H-NMR (CDCl₃): δ [ppm]=7.70-7.63 (m, 4H, PhSi); 7.38-7.31 (m, 6H,PhSi); 5.88-5.76 (m, 1H, CH₂═CH); 5.32-5.26 (m, 2H, H-1 & H-2); 5.24,5.18 (dm, 1H, J_(vic,trans)=16.88 Hz, CH₂═CH); 5.15, 5.12 (d_(m), 1H,J_(vic,cis)=10.57 Hz, CH₂═CH); 4.904.87 (m, 1H, CHCH₃ EE); 4.10-3.42 (m,10.5H, H-3, H4, H-5, H-6a/b, ═CH—CH₂, CH₃CH₂O EE & CH₂N Cya); 3.22-3.16(m, 0.5H, H-5); 2.74-2.70 (m, 2H, SCH₂ Cya); 2.67, 2.65 (2×s, 4H, CH₂COSuc); 2.10, 2.09 (2×s, 3H, CH₃ Ac); 1.24-1.20 (m, 3H, CHCH₃ EE); 1.15(t, 1.5H, J_(gem)=7.05 Hz, CH₃CH₂O EE ); 1.04, 1.02 (2×s 9H, CH₃ tBuSi);0.89 (t, 1.5H, J_(gem)=7.05 Hz, CH₃CH₂O EE).

The hydrolysis of the ester is carried out as described in the case ofglucose.

General Procedures for Synthesis on Polymeric Supports

General Procedure for the Coupling of the Thioglycosides to theAmino-functionalized Polymeric Supports

A solution of 14.6 mmol of a thioglycoside is shaken overnight in asolid-phase reactor with 15.4 g (19.8 mmol, 1.28 mmol/g) ofaminomethylpolystyrene, 3.7 ml (14.6 mmol) of diisopropylcarbodiimideand 3.86 g (14.6 mmol) of N-hydroxylbenzotriazole. The resin is thenfiltered off with suction and washed ten times with 50 ml each of DMFand dichloromethane. The loaded polymer is dried in vacuo and theloading with carbohydrate matrix is determined by means of elementalanalysis. As a rule, the loading is 50-80% of the maximally possibleloading.

General Procedure for the Removal of the Glycoside Derivatives from thePolymeric Support

a) analytical: A suspension of 80 mg, (0.056 mmol) of polymer-bondedderivative in 1.5 ml of abs. dichloromethane is shaken at roomtemperature in a 5 ml PE syringe (PE frit, plastic cap) with 0.3 ml of a3.5 percent solution of bromine in abs. dichloromethane and 0.08 ml (0.[lacuna] mmol) of 2,6-di-tert-butylpyridine or a corresponding amount ofpolymer-bonded 2,6-di-tert-butylpyridine. After 15 min, 0.2 ml ofcyclohexene, 0.2 ml of the abs. alcohol to be glycosylated and 25 mg(0.056 mmol) of tetraethylammonium bromide are added. After 2.5 h, theresin is filtered off and washed five times with 1 ml ofdichloromethane. The combined filtrates are freed from the solvent invacuo. The crude product obtained is applied to a silica gel cartridgein a little dichloromethane. It is eluted first with 30 ml of petroleumether. This fraction is discarded. The product is obtained by elutingwith petroleum ether/ethyl acetate (1:1). Characterization by HPLC andMS analysis follows.

b) preparative: A suspension of 400 mg (0.312 mmol) of polymer-bondedgalactose derivative in 3 ml of abs. dichloromethane is shaken at roomtemp. in a 5 ml PE syringe (PE frit, plastic cap) with 1.2 ml of a 3.5percent solution of bromine in abs. dichloromethane and 0.32 ml (0.[lacuna] mmol) of 2,6-di-tert-butylpyridine. After 15 min, the resin isfiltered off and washed five times with 3 ml of dichloromethane eachtime. 0.5 ml of cyclohexene, 0.5 ml of the abs. alcohol to beglycosylated and 25 mg (0.056 mmol) of tetraethylammonium bromide areadded to the filtrate. The organic phase is washed with water, driedover magnesium sulfate and concentrated in vacuo, and the residue ispurified by flash chromatography on silica gel.

General Procedure for the Alkylation of the Glycosides on the PolymericSupport with Potassium tert-Butoxide

A solution of 87 mg (0.78 mmol) of potassium tert-butoxide in abs. DM,Fis added to a suspension of 100 mg (0.078 mmol) of loaded polymer in 1.5ml of abs. DMF. The mixture is shaken for 15 min. It is filtered and,the Filtrate is discarded. 0.78 mmol of the appropriate alkylating agentin 1.5 ml of abs. DMF is then added and the mixture is shaken for 4 h.The resin is separated from the solution and washed five times with 2 mleach of DMF, toluene and dichloromethane.

General Procedure for the Alkylation of the Galactosides on thePolymeric Support with tert-Butyl-P₄ Base (Schwesinger Base)

A solution of 0.22 ml (0.22 mmol) of tert-butyl-P₄ base in abs. DMF isadded to a suspension of 80 mg (0.056 mmol) of loaded polymer in 1.5 mlof abs. DMF. The mixture is shaken for 10 min. 0.56 mmol of theappropriate alkylating agent is then added and the mixture is shaken for2-4 h. The resin is filtered off with suction from the solution andwashed five times with 2 ml each of DMF, toluene and dichloromethane.

General Procedure for the Removal of the Acetate Protective Group on thePolymeric Support

0.3 ml of a 30% strength sodium methanolate solution is added to, auspension of 0.0050 mmol of loaded polymer in 2 ml of ioxane/methanol.The mixture is shaken at room temperature for 3 h. The resin is filteredoff with suction from the solution and first washed five times withmethanol/dioxane and then five times with 2 ml each of DMF anddichloromethane.

General Procedure for the Removal of the tert-ButyldiphenylsilylProtective Group on the Polymeric Support

0.56 ml (0.56 mmol, 1M) of tetrabutylammonium fluoride in THF is addedto a suspension of 0.056 mmol of loaded polymer in 1.5 ml of THF. Themixture is shaken for 4 h. The resin is filtered off with suction fromthe solution and washed five times with 2 ml each of DMF anddichloromethane.

General Procedure for the Removal of the Ethoxyethyl Ether ProtectiveGroup on the Polymeric Support

para-Toluenesulfonic acid is added to a suspension of 0.050 mmol ofloaded polymer in 1.5 ml of dioxane/methanol and the mixture is stirredat 40° C. for 4 h. The resin is filtered off with suction from thesolution and washed with 0.5N HCl solution and then washed five timeswith 2 ml each of DMF and dichloromethane.

The isopropyl protective group can be removed under analogousconditions. The reaction times or temperatures may change in this case.

General Procedure for the Removal of the Allyl Ether Protective Group onthe Polymeric Support

A solution of 198 mg of zirconocene dichloride and 0.63 ml of BuLi (1.7M) in THF is added at −70° C. to a suspension of 0.060 mmol of loadedpolymer in 1.5 ml of THF. The mixture is stirred at room temperature for4 h after addition is complete. The resin is filtered off with suctionfrom the solution and washed with 0.5N HCl solution and then washed fivetimes with 2 ml each of DMF and dichloromethane.

Example 20 Methyl2-O-methyl-6-O-tert-Butyldiphenylsilyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with methyl iodideaccording to the general working procedure for an alkylation. Afterfiltration on silica gel, 16 mg of a colorless oil are obtained. Theproduct is purified by preparative HPLC and individual fractions areidentified by mass spectrometric analysis and NMR spectra.

R_(f)=0.45, 0.34 (PE/EtOAc=4:1 v/v). FBA-MS (NBA-pos, LiCl): (m/e)=495.2(100%, [M+Li]⁺, calc.: 295;2); 496.2 (26%, [M+Li]⁺, C, ca3c.: 496.2).

Example 21 Methyl2-O-benzyl-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-gluco-pyranoside

166 mg (0.1 mmol) of the polymer are reacted with benzyi bromideaccording to the general working procedure for an alkylation and thecarbohydrate is removed from the resin. After filtration on silica gel,15 mg of a colorless oil are obtained. The product is purified bypreparative HPLC and individual fractions are identified by massspectrometric analysis and NMR spectra.

R_(f)=0.53, 0.47 (PE/EtOAc=4:1 v/v). C₃₃H₄₄O₆Si (564.8) FBA-MS (NBA-pos,LiCl): (m/e)=571.1 (100%, [M+Li]⁺, calc.: 571.3); 572.1 (35%, [M+Li]⁺,¹³C, calc.: 572.3).

Example 22 Methyl2-O-propyl-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-gluco-pyranoside

166 mg (0.1 mmol) of the polymer are reacted with n-propyl iodideaccording to the general working procedure for an alkylation and thecarbohydrate is removed from the resin. After filtration on silica gel,18 mg of a colorless oil are obtained.

R_(f)=0.49, 0.46 (PE/EtOAc=4:1 v/v). C₂₉H₄₄O₆Si (516.8) FBA-MS (NBA-pos,LiCl): (m/e) 523.3 (100%, [M+Li]⁺, calc.: 523.2); 524.3 (33%, [M+Li]⁺,calc.: 524.2).

Example 23 Methyl2-O-(2′-Naphthyl)methyl-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with (2-naphthyl)methylenebromide according to the general working procedure for an alkylation andthe carbohydrate is removed from the resin. After filtration on silicagel, 22 mg of a slightly yellowish oil are obtained. It was possible todetect the desired product by mass spectrometry.

Example 24 Methyl2-O-Isopropyl-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-glucopyranoside

66 mg (0.1 mmol) of the polymer are reacted with 2-propyl bromideaccording to the general working procedure for an alkylation and thecarbohydrate is removed from the resin. After filtration on silica gel,17 mg are obtained. The product can be detected by mass spectrometry.

HPLC (gradient 54180): Rt (min)=3.61 (15.3%, DTBpy); 14.2 (11.0%, 2-OH);15.7 (19.2%).

Example 25 Methyl2-O-(4′-Cyanobenzyl)-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with o-cyanobenzyl bromideaccording to the general working procedure for an alkylation and thecarbohydrate is removed from the resin. After filtration on silica gel,22 mg of a slightly yellowish oil are obtained. Rf=0.52, 0.47(PElEtOAc=4:1 v/v).

C₃₃H₄₃NO₆Si (577.8) FBA-MS (NBA-pos, LiCl): (m/e)=241.1 (69%); 596.3(38%, [M+Li]⁺, calc.: 596.4); 597.3 (22%, [M+Li]⁺, C, calc.: 597.4);746.4 (66%, [M+C₄H₈ ⁷⁹BrO+H]⁺, calc.: 746.4); 747.4 (64%, [M+C₄H₈⁷⁹BrO+H]⁺, ¹³C, calc.: 747.4); 748.4 (100%, [M+C₄H₈ ⁸¹BrO+H]⁺, calc.:748.4); 749.4 (57%, [M+C₄H₈ ⁸¹BrO+H]⁺, C, calc.: 749.4).

Example 26 Methyl2-O-heptyl-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with 1-iodoheptaneaccording to the general working procedure for an alkylation and thecarbohydrate is removed from the resin. After filtration on silica gel,25 mg of a colorless oil are obtained.

R_(f)=0.65, 0.49 (PE/EtOAc=4:1 v/v). C₃₃H₄₃NO₆Si (577.79); FBA-MS(NBA-pos, LiCl): (m/e)=241.1 (100%); 579.4 (74%, [M+Li]⁺, calc.: 579.4);580.4 (31%, [M+Li]⁺, C, calc.: 580.4); 729.4 (72%, [M+C₄H8⁷⁹BrO+H]⁺,calc.: 729.4); 730.4 (38%, [M+C₄H₈ ⁷⁹BrO+H]⁺, ^(—)C, calc.: 730.4);731.4 (79%, [M+C₄H₈ ⁷⁹BrO+H]⁺, calc.: 731.4); 732.4 (34%, [M+C₄H₈⁸¹BrO+H]⁺, C, calc.: 723.4).

Example 27 Methyl2-O-(2′-methoxy-5′-nitrobenzyl)-6-O-tert-butyldiphenylsilyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with2-methoxy-5-nitrobenzyl bromide according to the general workingprocedure for an alkylation and the carbohydrate is removed from theresin. After filtration on silica gel, 15 mg of a slightly yellowish oilare obtained.

R_(f)=0.48, 0.43 (PE/EtOAc=4:1 v/v). C₃₃H₄₅NO₉Si (627.8).

Example 28 Methyl 2-O-methyl-6-O-benzyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with methyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is alkylated with benzylbromide. After removal of the carbohydrate from the resin and filtrationon silica gel, 24 mg of a colorless oil are obtained. For confirmedcharacterization of the product and assignment of the two anomers, theproduct was purified by preparative HPLC (gradient 90/10).

C₁₈H₂₈O (340.4); R_(f)=0.63, 0.54 (PE/EtOAc=3:1 v/v). 400 MHz-¹H-NMR(CDCl₃): δ [ppm]=7.32-7.31 (m, 5H, Ph); 4.83 (d, 1H, J_(2.1)=3.81 Hz,H-1); 4.60 (d, 1H, J_(gem)=12.32 Hz, CH₂Ph); 4.55 (d, 1H, J_(gem)=12.03Hz; CH₂Ph); 4.20 (dd, 0.3H, J_(1.2)=3.23 Hz, J_(3.2)=12.03 Hz, =H-2),4.12 (dd, 0.7H, J_(1.2)=2.94 Hz, J_(3.2)=11.45 Hz, H-2); 4.00 (dd, 0.3H,J_(vic)=11.89 Hz, J_(gem)=6.61 Hz, OCH₂ Pr); 3.92 (dd, 0.7H,J_(vic)=11.44 Hz, J_(gem)=7.34 Hz, OCH₂ Pr); 3.83-3.82 (m, 1.6H,H-6a/b); 3.81-3.39 (m, 8.4 Hz, H-3, H-4, H-6b); 3.47, 3.41 (2×s, 6H,OCH₃); 3.23-3.21 (m, 1H, H-5); 1.91 (s_(b), 1H, OH); 1.61-1.54 (m, 2H,OCH₂CH₂ Pr); 0.91 (t, 3H, J_(gem)=7.34 Hz, CH₃ Pr);

Example 29 Benzyl 2-O-methyl-6-O-methyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with methyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withmethyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 20 mg of a colorless oil are obtained.

R_(f)=0.46, 0.34, 0.1 (OH) (PE/EtOAc=3:1vv). C₁₈H₂₈O₆ (340.4); FBA-MS(NBA-pos, LiCl): (m/e)=233.1 (Gly⁺, calc.: 233.1); 347.0 ([M+Li]⁺,calc.: 347.2); 497.2 ([M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 497.2); 499.2 ([M+C₄H₈⁸¹BrO+Li]⁺, calc.: 497.2).

Example 30 Methyl2-O-methyl-6-O-heptyl-3-O-propyl-(α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with methyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withheptyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 27 mg of a colorless oil are obtained.

R_(f)=0.53, 0.42 (PE/EtOAc=3:1 v/v). C₁₈H₃₆O₆ (348.5); FBA-MS (NBA-pos,LiCl): (m/e)=7355.2 (22%, [M+Li]⁺, calc.: 355.2); 369.2 (88%); 505.2(100%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 505.2); 507.2 (99%, [M+C₄H₈⁸¹BrO+Li]⁺, calc.: 507.2).

Example 31 Isopropyl2-O-methyl-6-O-heptyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with methyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withheptyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 21 mg of a colorless oil are obtained.

R_(f)=0.69, 0.63 (PE/EtOAc=3:1 v/v). C₂₀H₄₀O₆ (376.5); FBA-MS (NBA-pos,LiCl): (m/e)=533.2 (100%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 533.2); 534.2 (28%,[M+C₄H₈ ⁷⁹BrO+Li]⁺, ^(—)C, calc.: 534.2); 535.2 (99%, [M+C₄H₈⁸¹BrO+Li]⁺, calc.: 535.2); 536.2 (26%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.:536.2).

Example 32 Ethyl2-O-methyl-6-O-(2′-Methoxy-5′-nitrobenzyl)-3-O-propyl-α,β-D-gluco-pyranoside

166 mg (0.1 mmol) of the polymer are reacted with methyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated with2-methoxy-5-nitrobenzyl bromide. After removal of the carbohydrate fromthe resin and filtration on silica gel, 10 mg of a colorless oil areobtained.

R_(f)=0.35, 0.27 (PE/EtOAc=3:1 v/v). C₁₈H₃₆O₆ (429.5); FBA-MS (NBA-pos,LiCl): (m/e)=384.1 (3%, Gly⁺, calc.: 384.2); 435.1 (22%); 436.1 (22%,[M+Li]⁺, calc.: 436.2); 586.1 (97%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 586.2);587.1 (36%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 387.2); 588.1 (100%, [M+C₄H₈⁸¹BrO+Li]⁺, calc.: 588.2); 589.1 (34%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.:589.2).

Example 33 Methyl2-O-benzyl-6-O-isopropyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with benzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated with2-bromopropane. After removal of the carbohydrate from the resin andfiltration on silica gel, 9 mg of a slightly yellowish oil are obtained.

R_(f)=0.62 (PE/EtOAc=3:1 v/v). C₂₀H₃₂O₆ (368.5); FBA-MS (NBA-pos, LiCl):(m/e)=301.1 (83%); 373.2 (19%); 525.2 (17%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.:525.2); 527.2 (15%, [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 527.2); 573.2 (13%);575.2 (17%); 667.3 (21%); 669.3 (19%).

Example 34 Ethyl2-O-benzyl-6-O-(4′-Cyanobenzyl)-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with benzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated with4-cyanobenzyl bromide. After removal of the carbohydrate from the resinand filtration on silica gel, 25 mg of a colorless oil are obtained.

R_(f)=0.66, 0.55 (PE/EtOAc=3:1 v/v). C₂₆H₃₃NO₆ (455.6); FBA-MS (NBA-pos,LiCl): (m/e)=410.2 (5%, Gly⁺, calc.: 410.2); 462.2 (34%, [M+Li]⁺, calc.:462.2); 587.2 (13%, ⁷⁹Br); 589.2 (13%, ⁸¹Br); 612.2 (97%, [M+C₄H₈BrO+Li]⁺, calc.: 612.2); 613.2 (43%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.:613.2); 614.2 (100%, [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 614.2); 615.2 (32%,[M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 615.2); 654.2 (11%, ⁷⁹Br); 656.2 (13%,⁸¹Br).

Example 35 Methyl 2-O-benzyl-6-O-heptyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with benzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withheptyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 32 mg of a colorless oil are obtained.

R_(f)=0.82, 0.76 (PE/EtOAc=3:1 v/v). C₂₄H₄₀NO₆ (424.6); FBA-MS (NBA-pos,LiCl): (m/e)=431.3 (14%, [M+Li]⁺, calc.: 431.2); 581.2 (100%, [M+C₄H₈⁷⁹BrO+Li]⁺, calc.: 581.3); 582.2 (40%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.:582.3); 583.2 (100%, [M+C₄H₅ ⁸¹BrO+Li]⁺, calc.: 583.3); 584.2 (30%,[M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 584.3).

Example 36 Isopropyl2-O-benzyl-6-O-cyclohexylmethyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with benzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withcyclohexylmethylene bromide. After removal of the carbohydrate from theresin and filtration on silica gel, 15 mg of a colorless oil areobtained.

R_(f)=0.85, 0.61 (PE/EtOAc=3:1 v/v). C₂₆H₄₂O₆ (450.6); FBA-MS (NBA-pos,LiCl): (m/e)=301.1 (59%); 443.3 (47%); 457.3 (34%, [M+Li]⁺, calc.:457.3); 517.2 (22%, ⁷⁹Br); 519.2 (22%, Br); 607.2 (98%, [M+C₄H₈⁷⁹BrO+Li]⁺, calc.: 607.3); 608.2 (42%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.:608.3); 609.2 (100%, [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 609.3); 610.2 (34%,[M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 610.3); 669.4 (22%).

Example 37 Methyl2-O-propyl-6-O-(4′-Cyanobenzyl)-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with n-propyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated with4-cyanobenzyl bromide. After removal of the carbohydrate from the resinand filtration on silica gel, 17 mg of a colorless oil are obtained.

R_(f)=0.63, 0.53 (PE/EtOAc=3:1 v/v). C₂₅H₃₁NO₆ (393.5); FBA-MS (NBA-pos,LiCl): (m/e)=382.0 (9%, ⁷⁹Br); 384.0 (9%, ⁸¹Br); 400.2 (28%, [M+Li]⁺,calc.: 400.2); 414.2 (11%); 442.2 (11%); 477.2 (9%, ⁷⁹Br); 479.2 (9%,⁸¹Br); 515.2 (9%); 550.2 (100%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 550.2); 551.2(36%, [M+C₄H₈ ⁷⁹BrO+Li]+, ¹³C, calc.: 551.2); 552.2 (98%, [M+C₄H₈⁸¹BrO+Li]⁺, calc.: 552.2); 553.2 (28%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.:553.2).

Example 38 Isopropyl2-O-propyl-6-O-benzyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with n-propyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withbenzyl bromide. After removal of the carbohydrate from the resin andfiltration on silica gel, 18 mg of a colorless oil are obtained.

R_(f)=0.73, 0.64 (PE/EtOAc=3:1 v/v). C₂₂H₃₆O₆ (396.5); FBA-MS (NBA-pos,LiCl): (m/e)=229.1 (94%); 389.2 (66%); 403.2 (43%, [M+Li]⁺, calc.:403.3); 445.2 (19%); 505.2 (27%, ⁷⁹Br); 507.2 (27%, ⁸¹Br); 553.2 (82%,[M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 553.2); 554.2 (33%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C,calc.: 554.3); 555.2 (85%, [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 555.3); 556.2(26%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 556.3).

Example 39 Benzyl 2-O-propyl-6-O-methyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with n-propyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withmethyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 149 mg of a colorless oil are obtained. Theproduct contains still larger amounts of benzyl alcohol.

R_(f)=0.46, 0.40 (PE/EtOAc=3:1 v/v). C₂₀H₃₂O₆ (368.5); FBA-MS (NBA-pos,LiCl): (m/e)=261.2 (8%, Gly⁺, calc.: 261.2); 375.2 (25%; [M+Li]⁺, calc.:375.2); 525.2 (15%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 525.2); 526.2 (5%,[M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 526.2); 527.2 (15%, [M+C₄H₈ ⁸¹BrO+Li]⁺,calc.: 527.2); 528.2 (4%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 528.2).

Example 40 Methyl 2-O-propyl-6-O-heptyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with n-propyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withheptyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 24 mg of a colorless oil are obtained.

R_(f)=0.58, 0.51 (PE/EtOAc=3:1 v/v). C₂₀H₄₀O₆ (376.5); FBA-MS (NBA-pos,LiCl): (m/e)=383.3 (35%; [M+Li]⁺, calc.: 383.3); 397.3 (100%); 439.3(28%); 453.4 (48%).

Example 41 Ethyl 2-O-pentyl-6-O-heptyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with pentyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withheptyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 20 mg of a colorless oil are obtained.

R_(f)=0.87, 0.80 (PE/EtOAc=3:1 v/v). C₂₃H₄₆O₆ (418.3); FBA-MS (NBA-pos,LiCl): (m/e)=425.3 (76%; [M+Li]⁺, calc.: 452.3); 426.3 (19%, [M+Li]⁺,¹³C, calc.: 426.3); 575.3 (100%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 575.3);576.3 (38%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 576.3); 577.3 (98%, [M+C₄H₈⁸¹BrO+Li]⁺, calc.: 577.3); 578.3 (28%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.:578.3).

Example 42 Isopropyl2-O-pentyl-6-O-methyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with pentyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withmethyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 18 mg of a colorless oil are obtained.

R_(f)=0.67, 0.64 (PE/EtOAc=3:1 v/v). C₁₈H₃₆O₆ (348.3); FBA-MS (NBA-pos,LiCl): (m/e) 341.0 (100%); 355.1 (62%; [M+Li]⁺, calc.: 355.2); 505.2(83%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 505.2); 506.2 (28%, [M+C₄H₈ ⁷⁹BrO+Li]⁺,¹³C, calc.: 506.2); 507.2 (80%, [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 507.2); 508.2(19%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 508.2).

Example 43 Benzyl2-O-heptyl-6-O-cyclohexylmethyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with heptyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withcyclohexylmethylene bromide. After removal of the carbohydrate from theresin and filtration on silica gel, 136 mg of a colorless oil areobtained. The product contains still larger amounts of benzyl alcohol.

R_(f)0=.77, 0.67 (PE/EtOAc=3:1 v/v). C₃₀H₅₀O₆ (506.7); FBA-MS (NBA-pos,LiCl): (m/e)=285.2 (65%); 309.2 (100%); 339.2 (45%); 399.3 (39%, Gly⁺,calc.: 399.3); 451.3 (48%); 513.3 (22%; [M+Li]⁺, calc.: 513.3); 663.3(24%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 663.3); 665.3 (34%, [M+C₄H₈ ⁸¹BrO+Li]⁺,calc.: 665.3).

Example 44 Methyl 2-O-heptyl-6-O-benzyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with heptyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withbenzyl bromide. After removal of the carbohydrate from the resin andfiltration on silica gel, 32 mg of a colorless oil are obtained.

R_(f)=0.86, 0.77 (PE/EtOAc=3:1 v/v). C₂₄H₄₀O₆ (424.6); FBA-MS (NBA-pos,LiCl): (m/e)=341.2 (7%; [6-OH+Li]⁺, calc.: 341.3); 431.3 (13%, [M+Li]⁺,calc.: 413.3); 459.2 (15%, ⁷⁹Br); 461.3 (14%, ⁸¹Br); 491.2 (16%,[6-OH+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 491.3); 493.2 (15%,. [6-OH+C₄H₈⁸¹BrO+Li]⁺, calc.: 493.3); 581.2 (95%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.:581.3); 582.3 (38%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 582.3); 583.2 (100%,[M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 583.2); 584.2 (31%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C,calc.: 584.3); 589.2 (68%, ⁷⁹Br); 590.2 (25%, ⁷⁹Br, ¹³C); 591.2 (64%,⁸¹Br); 592.2 (19%, ⁸¹Br, ¹³C).

Example 45 Isopropyl 2-O-heptyl6-O-(4′-Cyanobenzyl)-3-O-propyl-D-α,β-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with heptyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated with4-cyanobenzyl bromide. After removal of the carbohydrate from the resinand filtration on silica gel, 21 mg of a colorless oil are obtained.

R_(f)=0.76, 0.74 (PE/EtOAc=3:1 v/v). C₂₇H₄₃NO₆ (477.6); FBA-MS (NBA-pos,LiCl): (m/e)=408.2 (10%; Gly⁺, calc.: 408.2); 470.3 (20%); 484.3 (21 %,[M+Li]⁺, calc.: 484.3); 582.4 (22%); 617.3 (24%, ⁷⁹Br); 619.3 (24%,⁸¹Br); 634.2 (85%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 634.3); 635.2 (38%,[M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 635.3); 636.2 (92%, [M+C₄H₈ ⁸¹BrO+Li]⁺,calc.: 636.3); 637.2 (31%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 637.3).

Example 46 Methyl2-O-heptyl-6-O-isopropyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with heptyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withn-propyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 13 mg of a colorless, oil are obtained.

R_(f)=0.80, 0.72 (PE/EtOAc=3:1 v/v). C₂₀H₄₀O₆ (376.5); FBA-MS (NBA-pos,LiCl): (m/e)=383.3 (36%, [M+Li]⁺, calc.: 383.3); 397.3 (76%); 533.3(19%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 533.3); 535.3 (16%, [M+C₄H₈ ⁸¹BrO+Li]⁺,calc.: 535.3); 611.2 (40%).

Example 47 Methyl2-O-heptyl-6-O-(4′-Bromobenzyl)-3-O-propyl-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with heptyl iodideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated with4-bromobenzyl bromide. After removal of the carbohydrate from the resinand filtration on silica gel, 16 mg of a colorless oil are obtained.

R_(f)=0.84, 0.73 (PE/EtOAc=3:1 v/v). C₂₄H₃₉BrO₆ (503.5); FBA-MS(NBA-pos, LiCl): (m/e)=453.4 (100%); 509.2 (41%, [M+Li]⁺, ⁷⁹Br, calc.:509.3); 511.2 (37%, [M+Li]⁺, ⁸¹Br, calc.: 511.3); 523.2 (84%, ⁷⁹Br);525.2 (83%, Br); 659.0 (34%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, Br, calc.: 659.3);661.0 (59%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ⁸¹Br, calc.: 661.3); 663.0 (31%, [M+C₄H₈⁸¹BrO+Li]⁺, Br, calc.: 663.3).

Example 48 Methyl 2-O-ethyl-6-O-benzyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with ethyl iodide accordingto the general working procedure for an alkylation. The TBDPS group issubsequently removed and the product is then alkylated with benzylbromide. After removal of the carbohydrate from the resin and filtrationon silica gel, 22 mg of a colorless oil are obtained.

R_(f)=0.82, 0.77 (PE/EtOAc=3:1 v/v). C₁₉H₃₀O₆ (354.4); FBA-MS (NBA-pos,LiCl): (m/e)=271.2 (7%, [6-OH+Li]⁺, calc.: 271.2); 361.3 (15%, [M+Li]⁺,calc.: 361.2); 421.2 (11%, [6-OH+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 421.2); 423.2(9%, [6-OH+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 423.2); 449.3 (38%); 451.3 (41%);511.3 (96%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 511.2); 512.3 (36%, [M+C₄H₈⁷⁹BrO+Li]⁺, ¹³C, calc.: 512.2); 513.3 (100%, [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.:513.2); 514.3 (26%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 514.2).

Example 49 Methyl 2-O-ethyl-6-O-(2′-Methoxy-5′-nitrobenzyl)-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with ethyl iodide accordingto the general working procedure for an alkylation. The TBDPS group issubsequently removed and the product is then alkylated with2-methoxy-5-nitrobenzyl bromide. After removal of the carbohydrate fromthe resin and filtration on silica gel, 15 mg of a colorless oil areobtained.

R_(f)=0.43 (PE/EtOAc=3:1 v/v). C₂₀H₃₁NO₉ (429.5); FBA-MS (NBA-pos,LiCl): (m/e)=436.2 (9%, [M+Li]⁺, calc.: 436.2); 586.1 (95%, [M+C₄H₈⁷⁹BrO+Li]⁺, calc.: 586.2); 587.1 (35%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.:587.2); 588.1 (100%; [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 588.2); 588.1 (28%,[M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C, calc.: 589.2).

Example 50 Benzyl 2-O-ethyl-6-O-heptyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with ethyl iodide accordingto the general working procedure for an alkylation. The TBDPS group issubsequently removed and the product is then alkylated with methyliodide. After removal of the carbohydrate from the resin and filtrationon silica gel, 116 mg of a colorless oil are obtained. The productcontains still larger amounts of benzyl alcohol.

R_(f)=0.61, 0.54 (PE/EtOAc=3:1 v/v). C₂₅H₄₂O₆ (438.6); FBA-MS (NBA-pos,LiCl): (m/e)=445.3 (29%, [M+Li]⁺, calc.: 445.3); 595.3 (100%, [M+C₄H₈⁷⁹BrO+Li]⁺, calc.: 595.3); 596.3 (40%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.:596.3); 597.3 (98%; [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 597.3); 598.3 (31 %,[M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C calc.: 595.3).

Example 51 Ethyl2-O-(2′-Cyanobenzyl)-6-O-heptyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with 2-cyanobenzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withheptyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 26 mg of a colorless oil are obtained.

R_(f)=0.78, 0.70 (PE/EtOAc=3:1 v/v). C₂₆H₄₁NO₆ (463.6); FBA-MS (NBA-pos,LiCl): (m/e)=418.2 (12%, Gly⁺, calc.: 418.3); 470.3 (100%, [M+Li]⁺,calc.: 470.3); 471.3 (32%, [M+Li]⁺, ¹³C, calc.: 471.3); 568.4 (78%);603.3 (15%, ⁷⁹Br); 605.3 (15%, ⁷⁹Br); 620.2 (57%, [M+C₄H₈ ⁷⁹BrO+Li]⁺,calc.: 620.3); 621.2 (25%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 621.3); 622.2(55%; [M+C₄H₈ ⁸¹BrO+Li]⁺, calc.: 622.3); 623.2 (19%, [M+C₄H₈ ⁸¹BrO+Li]⁺,¹³C, calc.: 623.3).

Example 52 Isopropyl2-O-(2′-Cyanobenzyl)-6-O-methyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with 2-cyanobenzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withmethyl iodide. After removal of the carbohydrate from the resin andfiltration on silica gel, 21 mg of a colorless oil are obtained.

R_(f)=0.52, 0.47 (PE/EtOAc=3:1 v/v). C₂₁ H₃₁NO₆ (393.5); FBA-MS(NBA-pos, LiCl): (m/e)=334.1 (8%, Gly⁺, calc.: 334.2); 386.2 (12%);400.2 (27%, [M+Li]⁺, calc.: 400.2); 414.2 (12%); 449.2 (10%, ⁷⁹Br);451.3 (10%; ⁸¹Br); 550.2 (98%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, calc.: 550.2); 551.2(36%, [M+C₄H₈ ⁷⁹BrO+Li]⁺, ¹³C, calc.: 551.2); 552.2 (100%; [M+C₄H₈⁸¹BrO+Li]⁺, calc.: 552.2): 553.2 (28%, [M+C₄H₈ ⁸¹BrO+Li]⁺, ¹³C calc.:553.2).

Example 53 Methyl2,4-di-O-benzyl-6-O-methyl-3-O-propyl-α,β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are converted into the derivativeanalogously to the experiments described above. For the removal of the1-ethoxyethyl protective group, the carbohydrate matrix is suspended ina mixture of 4 ml of dioxane, 0.4 ml of alcohol (methanol, propanol,octanol or benzyl alcohol) and a spatula-tipful of pyridiniumtoluene4-sulfonate. The syringe is then closed with a plastic cap andshaken at room temp. for 16 h. Following this, the resin is washed fivetimes with 3 ml of dioxane p.a. each time and twice with 3 ml of DMF.

After the removal of the 1-ethoxyethyl protective group, the 4-positionis alkylated with benzyl bromide and the carbohydrate is removed fromthe resin. 12-16 mg of a colorless oil are obtained. As all crudeproducts contain identical components according to TLC, HPLC and MS,they are combined and purified by chromatography on silica gel usingpetroleum ether/ethyl acetate (12:1).

C₂₅H₃₄O₆ (430.6); FAB-MS (NBA-pos, LiCl): (m/e)=437.1 (100%, [M+Li]⁺,calc.: 437.2); 438.1 (28%, [M+Li]⁺, ¹³C, calc: 438.2); 513.3 (28%,[C₃₁H₃₈O₆+Li]⁺, 6-OBn, calc: 506.3).

400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.50-7.25 (m, 10H, Ph); 4.86 (d, 1H,J_(gem)=10.86 Hz, CH₂Ph); 4.77 (d, 1H, J_(gem)=12.32, CH₂Ph); 4.60 (d,.1H, J_(gem)=12.03 Hz, CH₂Ph); 4.56 (d, 1H, J_(gem)=10.86 Hz, CH₂Ph);4.52 (d, 1H, J_(2.1)=3.81 Hz, H-1); 3.87-3.24 (m, 8H, H-2, H-3, H4, H-5,H-6a/b, OCH₂Pr); 3.32, 3.30 (2×s, 6H, OCH₃); 1.66-1.61 (m, 2H,OCH₂CH₂Pr); 0.92 (t, J_(gem)=7.48 Hz, CH₃Pr).

6-Benzyl Derivative:

400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.51-7.26 (m, 15H, Ph); 4.86 (d, 1H,J_(gem)=11.15 Hz, CH₂Ph); 4.80 (d, 1H, J_(gem)=10.57 Hz, CH₂Ph); 4.67(d, 1H, J_(gem)=11.15Hz, CH₂Ph); 4.614.54 (m, 2H, CH₂Ph); 4.50 (d, 1H,J_(gem)=10.57 Hz, CH₂Ph); 4.25-4.18 (m, 3H, H-1 & OCH₂Pr); 3.80-3.29 (m,6H, H-2, H-3, H4, H-5, H-6a/b); 3.54 (s, 3H, OCH₃); 1.68-1.60 (m, 2H,OCH₂CH₂Pr); 0.91-0.86 (m, 3H, CH₃Pr).

Example 54 Methyl2-O-benzyl-4-O-(2′-Bromo-1′-ethoxy)ethyl-6-O-methyl-3-O-propyl-α/β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are converted into the derivativeanalogously to the experiments described above. By treatment of theresin with various combinations of solvents and IM citric acid (4 ml ofDMF+0.4 ml of 1M citric acid; 4 ml of DMF+0.4 ml of 1M citric acid+4 hultrasound; 4 ml of DMF+0.04 ml of 1M citric acid; 4 ml of dioxane+0.04ml of 1M citric acid; 4 ml of CH₂Cl₂+1 ml of acetone+0.1 ml of 1M citricacid), it is attempted to remove the 1-ethoxyethyl protective group.

The resin is then subjected to a benzylation and the carbohydrate isremoved from the polymeric support. 13-17 mg of a colorless oil areobtained. As all crude products contain identical components accordingto TLC, HPLC and MS, they are combined and purified by chromatography onsilica gel using petroleum ether/ethyl acetate (8:1). C₂₂H₃₅BrO₇(491.4).

FAB-MS (NBA-pos, LiCl) of crude product: (m/e)=497.4 (100%, [M+Li]⁺,⁷⁹Br, calc.: 497.2); 498.4 (31%, [M+Li]⁺, ⁷⁹Br, C, calc. 498.2); 499.4(98%, [M+Li]⁺, ⁸¹Br, calc.: 499.2); 500.4 (22%, [M+Li]⁺, ⁸¹Br, ¹³C,calc.: 500.2); 573.2 (28%, [C₂₈H₃₉ ⁷⁹BrO₇+Li]⁺6-OBn, calc.: 573.3);575.2 (31%, [C₂₈H₃₉ BrO₇+Li]⁺6-OBn, calc.: 575.3).

1st Diastereomer:

400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.33-7.25 (m, 5H, Ph); 4.87-4.84 (m, 1H,CHCH₂EEBr); 4.72 (d, 1H, J_(gem)=12.03 Hz, OCH₂Ph); 4.64 (d, 1H,J_(2.1)=3.82 Hz, H-1); 4.56 (d, 1H, J_(gem)=12.03 Hz, OCH₂Ph); 3.90-3.85(m,1H, OCH₂); 3.75-3.54 (m, 6H, H-2, H-6a/b, OCH₂); 3.52 (s, 3H, OCH₃);3.48-3.31 (m, 5H, H-3, H4, H-5 & CH₂Br EEBr); 3.36 (s, 3H, OCH₃);1.63-1.57 (m, 2H, OCH₂CH₂Pr); 1.25-1.18 (m, 3H, OCH₂CH₃EEBr &); 0.89 (t,J_(gem)=7.49 Hz, CH₃Pr).

400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.34-7.26 (m, 5H, Ph); 4.97-4.95 (m, 1H,CHCH₂EEBr); 4.72 (d, 1H, J_(gem)=12.03 Hz, OCH₂Ph); 4.66 (d, 1H,J_(2.1)=3.52 Hz, H-1); 4.56 (d, 1H, J_(gem)=12.03 Hz, OCH₂Ph); 3.93-3.87(m, 1H, OCH₂); 3.70-3.57 (m, 6H, H-2, H-6a/b, OCH₂); 3.54-3.30 (m, 5H,H-3, H-4, H-5 & CH₂Br EEBr); 3.49 (s, 3H, OCH₃); 3.36 (s, 3H, OCH₃);1.64-1.59 (m, 2H, OCH₂CH₂Pr); 1.23-1.19 (m, 3H, OCH₂CH₃EEBr &); 0.89 (t,J_(gem)=6.75 Hz, CH₃Pr). HPLC (gradient 90/10):

During chromatography, the derivative benzylated in the 6-position,methyl2,6-di-O-benzyl4-O-(2-bromo-1-ethoxy)-ethyl-3-O-propyl-Dgluco-pyranoside,which has already been observed in the FAB mass spectrum, can beseparated off.

C₂₈H₃₉BrO₇ (567.51); 400 MHz-¹H-NMR (CDCl₃): δ [ppm]=7.33-7.25 (m, 10H,Ph); 4.96-4.49 (m, 6H, H-1, OCH₂Ph & CHCH₂Br EEBr); 3.92-3.10 (m, 12H,H-2, H-3, H4, H-5, H-6a/b, OCH₂ & CH₂Br EEBr), 3.36, 3.33 (s, 3H, OCH₃);1.64-1.54 (m, 2H, OCH₂CH₂Pr); 1.25-1.19 (m, 3H, OCH₂CH₃EEBr &); 0.89 (t,J_(gem)=7.49 Hz, CH₃ Pr).

Example 55 Methyl2-O-benzyl4-O-tert-butyloxycarbonylmethyl-6-O-methyl-3-O-propyl-α/β-D-glucopyranoside

166 mg (0.1 mmol) of the polymer are reacted with benzyl bromideaccording to the general working procedure for an alkylation. The TBDPSgroup is subsequently removed and the product is then alkylated withmethyl iodide. After the 1-ethoxyethyl protective group has beenremoved, the product is reacted with tert-butyl bromoacetate. Afterremoval of the carbohydrate from the resin and filtration on silica gel,23 mg of a colorless oil are obtained. R_(f)=0.64, 0.59 (PE/EtOAc=3:1v/v). C₂₄H₃₈O₈ (454.6).

FAB-MS (NBA-pos, LiCl): (m/e)=461.3 (75%, [M+Li]⁺, calc.: 461.3); 462.3(23%, [M+Li]⁺, ¹³C, calc.: 462.3); 561.3 (100%,[C₂₉H₄₆O₁₀+Li]⁺6-OCH₂CO₂tBu, calc.: 561.3); 562.3 (33%, [C₂₉H₄₆O₁₀+Li]⁺,¹³C, calc.: 562.3).

Example 56

Library containing 1,2,6-functionalized glucose derivatives (compound ofthe formula I where X is equal to O, R³ is equal to propyl and R⁴ isequal to hydrogen).

80 mg of the loaded resin were functionalized according to the generalworking procedures (Table 1).

Example 57

Library containing 1,2,4,6-functionalized glucose derivatives (compoundof the formula I where X is equal to O, R¹ is equal to methyl, R³ isequal to propyl).

80 mg of the loaded resin are functionalized according to the generalworking procedures. The alkylation in the 4-position takes place by useof tert-butyl bromoacetate.

MS analysis (m/e) Compound R² R⁴ R⁵ (FAB, NBA + LiCl) 1 Bn Bn Me 437.1 2Bn CH₂CO₂tB Me 461.3

TABLE 1 MS analysis (m/e) Compound R² R⁵ R¹ (FAB, NBA + LiCl) 1 Me Bn Me347.2 2 Me Me Bn 347.2 3 Me Hep Me 355.2 4 Me Hep iPr 383.2 5 Me MNBnEtEt 436.1 6 Bn iPr Me 375.1 7 Bn Cbn Et 462.2 8 Bn Hep Me 431.3 9 Bn cHexiPr 457.3 10 Bn iBu Me 389.2 11 Pr Cbn Me 400.2 12 Pr Bn iPr 403.2 13 PrMe Bn 375.2 14 Pr Hep Me 383.3 15 Pent iPr Me 355.2 16 Pent Hep Et 425.317 Pent Me iPr 355.3 18 Hep cHex Bn 513.3 19 Hep Bn Me 431.3 20 Hep CbniPr 484.3 21 Hep iPr Me 383.3 22 Hep BrBn Me 509.2 23 Et Bn Me 361.3 24Et MNBn Me 436.2 25 Et Hep Bn 445.3 26 Cbr iPr Me 400.3 27 Cbr Hep Et470.3 28 Cbr Me iPr 400.2 Abbreviations: MNBn = 2-methoxy-5-nitrobenzyl,CBn = o-cyanobenzyl, Pent = pentyl, cHex = cyclohexylmethylene.

Example 58 MethylS-(6′-O-tert-Butyldiphenylsilyl-3′,4′-O-isopropylidene-β-D-galactopyranosyl-2′-O-methyl)-4-mercaptobutyrate(32)

A solution of 3.0 g (5.2 mmol) of 19 in 30 ml of THF is stirred at 0°C., for 45 min with 0.6 g (5.3 mmol) of potassium tert-butylate under anargon atmosphere and then treated with 0.38 ml (6.0 mmol) of methyliodide. As only slight conversion is discernible after a few hours bythin-layer chromatographic checking, the same amount of reagents isadded again. The precipitating solid is dissolved by addition of 15 mlof DMF. After stirring for 12 h, the solution is concentrated in vacuo,and the residue is codistilled with toluene and purified by flashchromatography on silica gel (column 18×6 cm, eluent petroleumether/ethyl acetate 10:1).

Yield 1.8 g (59%), colorless oil, [α]_(D) ²⁵=−15.90 (c=1, CHCl₃);R_(F)=0.34 (petroleum ether/ethyl acetate 8:1).

400MHz-¹H-NMR (CDCl₃): δ [ppm]=7.69-7.66; 7.41-7.33 (m, 10H, SiPh₂),4.28 (d, 1 H, J_(1.2)=9.7 Hz, 1′-H), 4.27 (dd, 1H, J_(4.3)=5.5 Hz,J_(4.5)=2.3 Hz, 4′-H), 4.09 (dd, 1H, J_(3.2)=7.0 Hz, J_(3.4)=5.6 Hz,3′-H), 3.89 (m, 2H, 6′-H_(a,b)), 3.79 (ddd, 1H, J_(5.4)=2.3 Hz,J_(5.6)≈J_(5.6b)=6.2 Hz, 5′-H), 3.59; 3.55 (2s, 6H, OCH₃), 3.17 (dd, 1H,J_(2.1)=10.0 Hz, J_(2.3)=6.8 Hz, 2′-H), 2.77 (dt, 1H, J_(vic)=6.5 Hz,J_(gem)=12.9 Hz, SCH_(a)), 2.64 (dt, 1H, J_(vic)=6.5 Hz, J_(gem)=12.9Hz, SCH_(b)), 2.39 (m_(c), 2H, CH₂COOMe), 1.91 (m_(c), 2H, SCH₂CH₂),1.50; 1.33 (2s, 6H, C(CH₃)₂), 1.03 (s, 9H, SiC(CH₃)₃. 100.6 MHz-¹³C-NMR(CDCl₃); δ [ppm]=173.3 (CO), 135.6; 135.5 (C_(p)-SiPh₂), 133.5; 133.4(C_(e)-SiPh₂), 129.7; 127.7; 127.6 (C_(o,m)-SiPh2), 109.7 (C(CH₃)₂),83.6; 81.8; 79.4; 76.8; 73.4; 62.8 (C-1′-C-6′), 59.7 (OCH₃), 51.4(COOCH₃), 32.7 (SCH₂), 29.6 (CH₂COOMe), 28.0 (C(CH₃)₂), 26.7(SiC(CH₃)₃), 26.2 (C(CH₃)₂), 25.0 (SCH₂CH₂),19.2 (SiC(CH₃)₃).

C₃₁H₄₄O₇SSi (588.8) Calc.: C 63.23 H 7.53 S 5.44 Found: C 63.09 H 7.61 S5.41

Example 59S-(6′-O-tert-Butyldiphenylsilyl-3′,4′-O-isopropylidene-β-D-galactopyranosyl)-4-mercaptobutyricAcid, Polymer-bonded (33, 34)

The thiogalactoside 19 is coupled to 0.390 g (0.6 mmol) ofaminomethylpolystyrene to give 33 according to the general procedure.

Loading according to the sulfur content of the elemental analysis:0.77-0.81 mmol/g.

The thiogalactoside 19 is coupled to 2.0 g (0.56 mmol) of Tentagel togive 34 according to the general procedure.

Loading (gravimetric): 0.20 mmol/g.

Example 60S-(6′-O-tert-Butyldiphenylsilyl-3′,4′-O-isopropylidene-2′-O-β-D-galactopyranosyl)4-mercaptobutyricAcid, Polymer-bonded (35, 36)

The 2-O-methylthiogalactoside 32 is coupled to 1.0 g (0.6 mmol) ofaminomethylpolystyrene to give 35 according to the general workingprocedure.

Loading according to the sulfur content of the elemental analysis: 0.78mmol/g.

The 2-O-methylthiogalactoside 32 is coupled to 2.0 g (0.56 mmol) ofTentagel to give 36 according to the general working procedure.

Loading (gravimetric): 0.27 mmol/g.

Example 61 Methyl6-O-tert-Butyldiphenylsilyl-3,4-O-isopropylidene-2-O-methyl-α/β-D-galactopyranoside

a) by removal of 35: According to the general procedure, 400 mg (0.312mmol) of 79 are treated with methanol as an alcohol. Purification iscarried out by flash chromatography on silica gel (column 18×4 cm,eluent petroleum ether/ethyl acetate 8:1).

Yield 70 mg (24%) of α-anomer, colorless oil; 134 mg (46%) of β-anomer,colorless oil. By washing the resin again and combining the washingswith the mixed fractions, a further 43 mg (15%) are obtained as ananomer mixture.

b) by removal of 36: According to the general procedure, 80 isglycosylated using methanol as an alcohol. Purification is carried outby flash chromatography on silica gel (column 18×4 cm, eluent petroleumether/ethyl acetate 8:1).

Yield 12 mg (4%) of c-anomer, colorless oil; 44 mg (15%) of β-anomer,colorless oil.

In addition, 47 mg (17%) of hydrolysis sugar are isolated as an anomermixture.

c) by alkylation with sodium hydride/methyl iodide: 370 mg (0.3 mmol) of33 are suspended in 15 ml of DMF/THF (1:1) and preliminarily shaken atroom temp. under an argon atmosphere for 20 min with 0.090 g (3.0 mmol)of sodium hydride (80% in mineral oil). After addition of 0.19 ml (3.0mmol) of methyl iodide, the mixture is shaken for 12 h, and the resin isfiltered off after addition of 5 ml of methanol and washed a number oftimes with DMF. Removal is carried out according to the generalprocedure using methanol as an alcohol. Purification is carried out byflash chromatography on silica gel (column 15×3 cm, eluent petroleumether/ethyl acetate 8:1).

Yield 92 mg (32%) of a-anomer, clear oil; 43 mg (15%) of β-anomer, clearoil.

In addition, 14 mg (5%) of α-anomer and 32 mg (11 %) of P-anomer of thenonalkylated methyl glycoside are isolated.

d) by alkylation with KOtBu/methyl iodide: as under c) at 0° C., 4 h.

Yield 55 mg (19%), clear oil, anomer mixture.

Example 62 Methyl6-O-tert-Butyldiphenylsilyl-3,4-O-isopropylidene-2-O-benzyl-β-D-galactopyranoside

a) by alkylation of 33 with sodium hydride/benzyl bromide: 768 mg (0.6mmol) of 33 are reacted as above with 180 mg (6.0 mmol) of sodiumhydride (80% in mineral oil) and 0.72 ml (6.0 mmol) of benzyl bromide atroom temp. under an argon atmosphere for 12 h and removed. Purificationis carried out by flash chromatography on silica gel (column 15×4 cm,eluent petroleum ether/ethyl acetate 15:1).

Yield 67 mg (20%) of a-anomer, clear oil; 26 mg (8%) of β-anomer, turbidoil.

In addition, 4 mg (2%) are obtained as an anomer mixture.

b) by alkylation of 34 with sodium hydride/benzyl bromide: 2.5 g (0.5mmol) of 34 are reacted as above with 900 mg (30.0 mmol) of sodiumhydride (80% in mineral oil) and 3.6 ml (30.0 mmol) of benzyl bromide atroom temp. under an argon atmosphere for 12 h and removed. Purificationis carried out by flash chromatography on silica gel (column 18×3 cm,eluent petroleum ether/ethyl acetate 10:1).

Yield 100 mg (37%) of anomer mixture, yellow oil.

c) by alkylation with potassium tert-butoxide/benzyl bromide: 640:mg(0.5 mmol) of 33 are swollen in 20 ml of DMF. After addition of 0.56 g(5.0 mmol) of potassium tert-butoxide, the mixture is shaken under anargon atmosphere for 20 min. 0.59 ml (5.0 mmol) of benzyl bromide and0.22 g (0.6 mmol) of tetrabutylammonium iodide are then added and themixture is shaken for 16 h. 20 ml of methanol are added, and the resinis filtered off and washed a number of times with DMF and absol. THF.The resin is dried in vacuo. Removal is carried out according to thegeneral procedure with methanol as an alcohol. Purification is carriedout by flash chromatography on silica gel (column 18×3 cm, eluentpetroleum ether/ethyl acetate 8:1).

Yield 124 mg (44%) of a-anomer, clear oil; 22 mg (8%) of β-anomer,colorless oil.

d) by alkylation with phosphazene base P₄-t-Bu/benzyl bromide: 384 mg(0.33 mmol) of 33 are swollen in 10 ml of DMF and cooled to 0° C. underan argon atmosphere. 1.32 ml (1.32 mmol, 1 M in n-hexane) of P₄-tert-Buare added and the mixture is shaken. After 15 min, 0.59 ml (5.0 mmol) ofbenzyl bromide is added and the mixture is shaken at 0° C. for 16 h. Theresin is filtered off and washed a number of times with DMF and absol.THF. After drying in vacuo, the compound is removed from the supportaccording to the general procedure using methanol as an alcohol.Purification is carried out by flash chromatography on silica gel(column 18×3 cm, eluent petroleum ether/ethyl acetate 10:1).

Yield 163 mg (85%) of anomer mixture (α,β about 5:1), colorless oil.

α-Anomer: [α]_(D) ²⁵=+44.9 (c=1, CHCl₃); R_(F)=0.20 (petroleumether/ethyl acetate 8:1)

β-Anomer: [α]_(D) ²⁵=+17.2 (c=1, CHCl₃); R_(F)=0.30 (petroleumether/ethyl acetate 8:1).

Example 63 Methyl2-O-(o-Cyanobenzyl)-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-α/β-D-galactopyranoside

400 mg (0.312 mmol) of 33 are reacted with o-cyanobenzyl bromideaccording to the general working procedure (variant A) and removed withmethanol under glycosylating conditions. The crude product is purifiedby flash chromatography on silica gel (column 20×2 cm, eluent petroleumether/ethyl acetate 12:1).

α-Anomer:

Yield 26 mg (14%), colorless oil, [α]_(D) ²⁵=+50.5 (c=1.0, CHCl₃);R_(F)=0.39 (petroleum ether/ethyl acetate 4:1), HPLC (column C, gradient1): 20.91 min.

β-Anomer:

Yield 12 mg (7%), colorless oil, [α]_(D) ²⁵=+19.6 (c=0.33, CHCl₃);R_(F)=0.46 (petroleum ether/ethyl acetate 4:1), HPLC (column C, gradient1): 20.91 min.

Example 64 Methyl2-O-(p-Bromobenzyl)-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-α/β-D-galactopyranoside

400 mg (0.312 mmol) of 33 are reacted with p-bromobenzyl bromideaccording to the general working procedure and the product is removedunder glycosylating conditions using methanol. The crude product ispurified by flash chromatography on silica gel (column 20×2 cm, eluentpetroleum ether/ethyl acetate 12:1).

α-Anomer:

Yield 12 mg (6%), colorless oil, [α]_(D) ²⁵=+38.4 (c=1.0, CHCl₃);R_(F)=0.17 (petroleum ether/ethyl acetate 12:1), HPLC (column C,gradient. 1): 22.13 min.

β-Anomer:

Yield 3 mg (2%), colorless oil, [α]_(D) ²⁵=+39.3 (c=0.1, CHCl₃);R_(F)=0.23 (petroleum ether/ethyl acetate 12:1), HPLC (column C,gradient 1): 22.13 min.

Example 65 Methyl2-O-ethyl-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-α/β-D-galactopyranoside

400 mg (0.312 mmol) of 33 are reacted with ethyl iodide according to thegeneral working procedure and the product is removed under glycosylatingconditions using methanol. The crude product is purified by flashchromatography on silica gel (column 15×2.5 cm, eluent petroleumether/ethyl acetate 12:1).

α-Anomer:

Yield 22 mg (14%), colorless oil, [α]_(D) ²⁵=+73.2 (c=1, CHCl₃);R_(F)=0.49 (petroleum ether/ethyl acetate 4:1), HPLC (column C, gradient1): 19.62 min.

β-Anomer:

Yield 10 mg (7%), colorless oil, [α]_(D) ²⁵=+1.1 (c=0.33, CHCl₃);R_(F)=0.49 (petroleum ether/ethyl acetate 4:1), HPLC (column C,gradient: 1): 19.62 min.

Example 66S-(2′-O-Benzyl-3′,4′-O-isopropylidene-α/β-D-galactopyranosyl)-4-mercaptobutyricAcid, Polymer-bonded

1 g (0.78 mmol) of 33 is alkylated with benzyl bromide according to: thegeneral procedure (variant A) and the silyl protective group is removed.The polymer is dried in vacuo.

Example 67 Methyl2-O-benzyl-6-O-(2′-Naphthylmethyl)-3,4-O-isopropyliden-α/β-D-galactopyranoside

400 mg (0.312 mmol) ofS-(2′-O-benzyl-3′,4′-O-isopropylidene-α/β-D-galactopyranosyl)-4-mercaptobutyricacid—polymer bonded are reacted with 2-bromomethylnaphthalene accordingto the general working procedures and the product is removed underglycosylating conditions using methanol. The pure product is obtained byflash chromatography on silica gel (column 20×2 cm, eluent petroleumether/ethyl acetate 4:1) as an anomer mixture in the ratio α:β=10:1.

Yield 40 mg (38%), yellow oil, [α]_(D) ²⁵=+79.2 (c=1, CHCl₃); R_(F)=0.25(petroleum ether/ethyl acetate 4:1), HPLC (column C, gradient: 1): 15.28min.

Example 68 Methyl2-O-propyl-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-α/β-D-galactopyranoside

400 mg (0.312 mmol) of 33 are reacted with propyl iodide according tothe general working procedure and the product is removed underglycosylating conditions using methanol. The crude product is purifiedby flash chromatography on silica gel (column 17×2.5 cm, eluentpetroleum ether/ethyl acetate 12:1).

α-Anomer:

Yield 7 mg (5%), colorless oil, [α]_(D) ²⁵=+56.9 (c=0.2, CHCl₃);R_(F)=0.51 (petroleum ether/ethyl acetate 4:1), HPLC (column C, gradient1): 21.03 min.

β-Anomer:

Yield 2 mg (2%), colorless oil, [α]_(D) ²⁵=+2.7 (c=0.1, CHCl₃);R_(F)=0.57 (petroleum ether/ethyl acetate 4:1), HPLC (column C, gradient1): 19.62 min.

Example 69 Methyl2-O-heptyl-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-α/β-D-galactropyranoside

400 mg (0.312 mmol) of 33 are reacted with heptyl iodide with additionof 18-crown-6 according to the general working procedure (variant A) andthe product is removed under glycosylating conditions using methanol.The crude product is purified by flash chromatography on silica gel(column 20×2 cm, eluent petroleum ether/ethyl acetate 15:1).

α-Anomer:

Yield 12 mg (7%), colorless oil, [α]_(D) ²⁵=+52.6 (c=0.6, CHCl₃);R_(F)=0.34 (petroleum ether/ethyl acetate 10:1), HPLC (column C,gradient 1): 24.27 min.

β-Anomer:

Yield 8 mg (5%), colorless oil, [α]_(D) ²⁵=+14.6 (c=0.4, CHCl₃);R_(F)=0.40 (petroleum ether/ethyl acetate 10:1), HPLC (column C (C₈),gradient 1): 24.27 min.

Example 70 Ethyl 3,4-O-isopropylidene-1-thio-β-D-galactopyranoside

A mixture of 19.1 g (85.4 mmol) of ethyl 1-thio-β-D-galactopyranoside,360 ml (2.93 mol) of acetone dimethyl acetal and 0.3 g (16 mmol) ofp-toluenesulfonic acid monohydrate is stirred at room temp. After 18 h,1.2 ml of triethylamine are added and the mixture is concentrated todryness in vacuo. The residue is suspended in 180 ml of dichloromethaneand treated with 2.4 ml of 50% strength trifluoroacetic acid. After 15min, 3.6 ml of triethylamine are added and the mixture is concentratedin vacuo. The oil obtained is purified by flash chromatography on silicagel (column 30×10 cm, eluent petroleum ether/ethyl acetate 2:3).

Yield 15.7 g (70%), colorless crystals, melting point 89° C., [α]=+16.5°(c=1, CHCl₃); R_(F)=0.33 (petroleum ether/ethyl acetate 1:9).

Example 71 Ethyl6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-1-thio-β-D-galactopyranoside

A solution of 9.00 g (34 mmol) of Example compound 70 and 4.62 g (68mmol) of imidazole in 100 ml of absol. DMF is treated with 10.9 ml (43mmol) of tert-butyldiphenylsilyl chloride and stirred at room temp. for3 h. The reaction is terminated by addition of 50 ml of water. 150 ml ofdichloromethane are added and the organic phase is washed three timeswith 50 ml of water each time. The combined aqueous phases: areextracted with 100 ml of dichloromethane, the combined organic phasesare dried over magnesium sulfate and the solvent is removed in vacuo.The oil obtained is chromatographed on silica gel (column 20×5 cm,eluent petroleum ether/ethyl acetate 4:1). Yield 12.66 g (74%),colorless crystals, [α]_(D) ²⁵=+0.7° (c=1, CHCl₃); R_(F)=0.28 (petroleumether/ethyl acetate 4:1).

Example 72 Ethyl2-O-acetyl-3,4-O-isopropylidene-6-O-tert-butyldiphenylsilyl-1-thio-β-D-galactopyranoside

50 ml (520 mmol) of acetyl chloride are added dropwise with ice-coolingto a solution of 12.6 g (25 mmol) of Example compound 71 in 100 ml ofabsol. pyridine. After 18 h, the solvent is distilled off in vacuo, theresidue is taken up in 150 ml of dichloromethane, washed successivelywith 50 ml each of 0.5 N hydrochloric acid, satd sodiumhydrogencarbonate solution and satd sodium chloride solution and theorganic phase is dried over magnesium sulfate. After concentrating invacuo, the residue is separated from impurities by chromatography onsilica gel (column 25×5 cm, eluent petroleum ether/ethyl acetate 4:1).The oily product solidifies after several days.

Yield 13.6 g (83%), colorless crystals, melting point 76° C., [α]_(D)²⁵=+15.60 (c=1, CHCl₃); R_(F)=0.62 (petroleum ether/ethyl acetate 4:1).

Example 73 Ethyl2-O-acetyl-6-O-tert-butyldiphenylsilyl-1-thio-β-D-galactopyranoside

a) by deacetalization with acetic acid: A solution of 140 mg (0.26 mmol)of Example compound 72 in 20 ml of 60% strength acetic acid is warmed to60° C. for 2 h with stirring. The mixture is concentrated in vacuo andcodistilled with 10 ml of toluene. The residue is taken up in 20 ml ofdichloromethane and washed with 10 ml of satd sodium hydrogencarbonatesolution. The crude product is purified by chromatography on silica gel(column 15×2 cm, eluent petroleum ether/ethyl acetate 2:3).

Yield 59 mg (45%), colorless oil; the analytical data agree with thoseindicated under b).

b) by deacetalization with p-TsOH: 11.36 g (21 mmol) of Example compound72 are dissolved in 200 ml of chloroform, treated with 0.19 g (1 mmol)of p-toluenesulfonic acid monohydrate and 12.27 ml (146 mmol) ofethanedithiol and the mixture is heated under reflux. After 45 min, itis allowed to cool to room temp. and washed with 50 ml each of satdsodium hydrogencarbonate solution, 0.5 N hydrochloric acid and water.The organic phase is dried over magnesium sulfate and then freed fromthe solvent. Chromatographic purification (column 30×5 cm, eluentpetroleum ether/ethyl acetate 2:3) of the crude product yields the titlecompound after drying in vacuo.

Yield 8.44 g (80%), colorless oil solidifying after days, [α]_(D)²⁵=+9.4° (c=1, CHCl₃); R_(F)=0.39 (petroleum ether/ethyl acetate 1:1).

Example 74 Ethyl2-O-acetyl-3-O-allyl-6-O-tert-butyldiphenylsilyl-1-thio-β-D-galactopyranoside(28)

A solution of 8.33 g (165 mmol) of Example compound 73 and 4.31 g (173mmol) of dibutyltin oxide in 150 ml of benzene is heated under reflux ina water separator for 16 h. Half of the solvent is then removed bydistillation and 2.42 ml (286 mmol) of allyl bromide are added. Themixture is then stirred at 50° C. for 5 h. It is then concentrated invacuo, the residue is taken up in 150 ml of dichloromethane, and theorganic phase is washed three times with 50 ml of water each time anddried over magnesium sulfate. The solvent is concentrated in vacuo andthe crude product is purified by chromatography on silica gel (column25×8 cm, eluent petroleum ether/ethyl acetate 4:1).

Yield 7.34 g (82%), yellowish oil, [α]_(D) ²⁵=+2.4° (c=1, CHCl₃);R_(F)=0.35 (petroleum ether/ethyl acetate 4:1).

Example 75 Ethyl 2-O-acetyl-3-O-allyl-1-thio-β-D-galactopyranoside (29)

2.5 ml of a 1 M solution of tetrabutylammonium fluoride in THF are addeddropwise to a solution of 5.2 g (9.5 mmol) of 28 in 200 ml of THF andthe mixture is stirred at room temp. for 1 h. It is then diluted with500 ml of dichloromethane, washed with 100 ml of water and the organicphase is dried over magnesium sulfate. After concentrating, the crudeproduct is purified by chromatography on silica gel (column 20×5 cm,eluent petroleum ether/ethyl acetate 2:3).

Yield 2.29 g (79%), yellowish oil, [α]_(D) ²⁵=−20.6° (c=1, CHCl₃);R_(F)=0.35 (petroleum ether/ethyl acetate 4:1).

Example 76 Ethyl2-O-acetyl-3-O-allyl-6-O-p-(4′-methoxycarbonylbutyloxy)phenyl-1-thio-β-D-galactopyranoside(30)

A solution of 2.0 ml (13.5 mmol) of diethyl diazodicarboxylate in 5 mlof dichloromethane is added dropwise with stirring to a solution of 2.25g (9.5 mmol) of 29, 4.7 g (22.5 mmol) of methyl p-hydroxyphenoxybutyrateand 6.0 g (22.5 mmol) of triphenylphosphine in 70 ml of dichloromethane.After 4 h, the mixture is concentrated without further working up andthe crude product is purified by chromatography on silica gel (column20×4 cm, eluent petroleum ether/ethyl acetate 3:1).

Yield 1.92 g (53%), colorless oil, [α]_(D) ²⁵=+1.50° (c=1, CHCl₃);R_(F)=0.52 (petroleum ether/ethyl acetate 1:1).

Example 77 Ethyl2-O-acetyl-3-O-allyl-6-O-p-(4′-Methoxycarbonylbutyloxy)phenyl-4-O-β-(trimethylsilyl)ethoxymethyl-1-thio-β-D-galactopyranoside(31)

2.12 ml (12 mmol) of N,N-diisopropylethylamine and 1.59 ml (9 mmol) ofβ-(trimethylsilyl)ethoxymethyl chloride are added to a solution of 1.51g (3.02 mmol) of 30 in 20 ml of absol. dichloromethane. The reactionmixture is heated under reflux for 6 h under an argon atmosphere. Thereaction is then terminated by addition of 10 ml of methanol and themixture is concentrated in vacuo. Impurities are separated by means ofchromatography on silica gel (column 15×2 cm, eluent petroleumether/ethyl acetate 3:1).

Yield 1.8 g (90%), colorless oil, [α]_(D) ²⁵=−27.0° (c=1, CHCl₃);R_(F)=0.40 (petroleum ether/ethyl acetate 3:1).

Example 78 Preparation of Libraries of the Type Alkyl3,4-O-isopropylidene-2-O-alkyl-6-O-carbamoylgalactoside

a) General Procedure for the Coupling of the MethylGalactosylmercaptobutyrates to Amino-functionalized Polymeric Supports

1.9 g (30 mmol) of lithium hydroxide are added to a solution of 14.6mmol of the thiogalactoside in 400 ml of THF/methanol/water (2:2:1) andthe mixture is stirred at room temp. for 8 h. It is then neutralized(0.5 N hydrochloric acid or phosphate buffer solution), 400 ml of satdsodium chloride solution are added and the mixture is extracted threetimes with 200 ml of ethyl acetate. The extracts are dried overmagnesium sulfate and freed from the solvent in vacuo. The residue istaken up in 150 ml of dichloromethane or DMF and the solution obtainedis shaken overnight in a solid-phase reactor with 19.8 mmol of theamino-functionalized polymer concerned, 3.7 ml (14.6 mmol) ofN,N′-diisopropylcarbodiimide and 3.86 g (14.6 mmol) ofN-hydroxybenzotriazole. The polymer is then filtered off with suctionand washed ten times with 50 ml each of DMF and dichloromethane. Theloaded polymer is dried in vacuo and the loading with carbohydratematrix is determined by means of elemental analysis.

b) General Working Procedure for the Capping of the Polymers

A mixture of 1.56 mmol of the polymer concerned is shaken for 18 h witha solution of 0.45 ml (7.80 mmol) of acetic acid, 2.7 ml (15.60 mmol) ofN,N-diisopropylethylamine and 3.74 g (7.80 mmol) of PfPyU in 40 ml ofDMF. After filtering off the liquid phase with suction, the polymer iswashed thoroughly with DMF, dichloromethane and diethyl ether and driedin vacuo.

c) General Working Procedure for the Alkylation of Capped Polymers

0.078 mmol of the polymer concerned is shaken with a solution of 88 mg(0.78 mmol) of potassium tert-butoxide in 2 ml of DMF. After 15 min, thepolymer is filtered off and the resin is immediately [lacuna] with asolution of 41 mg (0.16 mmol) of 18-crown-6 and 0.78 mmol of the alkylhalide concerned in 2 ml of DMF. The mixture is shaken for 3 h and thepolymer is then filtered off with suction. The resin is washedthoroughly with DMF, methanol, dichloromethane and diethyl ether anddried in vacuo.

d) General Procedure for the Removal of the tert-ButyldiphenylsilylProtective Group on the Polymeric Support

0.56 ml (0.56 mmol, 1 M) tetrabutylammonium fluoride in THF is added toa suspension of 0.056 mmol of loaded polymer in 1.5 ml of THF. Themixture is shaken for 4 h. The resin is filtered off from the solutionand washed five times with 2 ml each of DMF and dichloromethane.

e) General Working Procedure for Carbamoylations

Variant A (Using 1,1′-Carbonyidiimidazole and Amines)

A solution of 0.25 g (1.56 mmol) of 1,1′-carbonyldiimidazole in 2 ml ofDMF or dioxane is added to 0.078 mmol of polymer with 0.1 ml (0.58 mmol)of N,N-diisopropylethylamine, a spatula-tipful of DMAP and aspatula-tipful of KOtBu. The mixture is shaken for 2 h and filtered. Thepolymer is then shaken overnight with a solution of 1.56 mmol of theappropriate amine in 2 ml of DMF. It is filtered and washed five timeseach with DMF and dichloromethane.

Variant B (Using Isocyanates)

A solution of 1.56 mmol of the appropriate isocyanate in 2 ml of dioxaneis added to 0.078 mmol of polymer. A spatula-tipful of DMAP is thenadded and the mixture is shaken for 3-7 h, depending on the reactivityof the OH group to be reacted. It is filtered and the polymer is washedthoroughly with dioxane, methanol and dichloromethane.

f) General Procedure for the Removal of the Galactose Derivatives fromthe Polymeric Support

A suspension of 0.056 mmol of polymer-bonded galactose derivative in 1.5ml of abs. dichloromethane is shaken at room temp. in a 5 ml PE syringe(PE frit, plastic cap) with 0.3 ml of a 3.5% strength (0.36 ml ofbromine to 10 ml of dichloromethane or 5-10 eq. of bromine) solution ofbromine in abs. dichloromethane and 0.08 ml (0.36 mmol) of2,6-di-tert-butylpyridine or a corresponding amount of polymer-bonded2,6-di-tert-butylpyridine. After 15 min, 0.2 ml of cyclohexene, 0.2 mlof the abs. alcohol to be glycosylated and 25 mg (0.056 mmol) oftetraethylammonium bromide are added. After 4 h, the resin is filteredoff and washed five times with 1 ml of dichloromethane. The combinedfiltrates are freed from the solvent in vacuo. The crude productobtained is applied to a silica gel cartridge in a littledichloromethane. The cartridge is eluted first with 30 ml of petroleumether. This fraction is discarded. The product is obtained by elutingwith suitable petroleum ether/ethyl acetate mixtures. If the mixture isdistributed in various alcohols, it is advantageously additionallyshaken with bromine solution and 2,6-di-tert-butylpyridine. The solutionis injected into a vessel from the syringe and washed 5x with abs.dichloromethane. This resulting mixture is distributed in variousvessels which contain the ammonium bromide, cyclohexene and therespective alcohol. The vessels are sealed and shaken. Standing for toolong in the air is to be avoided in the case of the bromine solutions,as these are moisture-sensitive.

Parallel Synthesis

6×3.1 g (2.42 mmol) of 33 are treated with PfPyU and acetic acidaccording to the general procedure. The resins thus obtained arealkylated with methyl iodide, ethyl iodide, heptyl iodide, benzylbromide, p-bromobenzyl bromide and o-cyanobenzyl bromide according tothe general procedure. The silyl protective group is then removedaccording to the general procedure. 150 mg each (about 0.119 mmol) ofthe resins obtained are then reacted either with diethylamine,benzytamine, methoxyethylamine, cyclopropylmethylamine or glycinetedt-butyl ester according to the general procedure or withp-chlorophenyl isocyanate, o-trifluoromethylphenyl isocyanate,o-nitrophenyl isocyanate, p-cyanophenyl isocyanate, m,p-dichlorophenylisocyanate, m-fluorophenyl isocyanate, phenyl isocyanate, n-propylisocyanate, tert-butyl isocyanate or ethyloxycarbonylmethyl isocyanateaccording to the general procedure. The polymers are swollen in 2 ml ofdichloromethane and shaken for 20 min with 0.9 ml in each case of a 3.5%strength bromine solution in dichloromethane and 0.24 ml (1.08 mmol) of2,6-di-tert-butylpyridine. The polymers are filtered off and washed anumber of times with dichloromethane. The solutions obtained are dividedinto three and shaken for 5 h each with 55 mg (0.26 mmol) oftetraethylammonium bromide, 0.2 ml of cyclohexene and 0.2 ml ofmethanol, ethanol or i-propanol. The solutions are concentrated invacuo. The residues are taken up in 250, jl of dichloromethane each andapplied to silica gel cartridges. They are washed with 30 ml each ofpetroleum ether and the eluate is discarded. They are then eluted with 5ml each of petroleum ether/ethyl acetate (1:1) and the product obtainedis concentrated in vacuo. By activation with CDl (variant A), thefollowing compounds of the formula (A) are obtained:

(A)

R² R⁵ R⁷ R¹ Yield R_(T) ^(a)) R_(F) ^(b)) 1 4-BrBn CH₃O(CH₂)₂ H Me 2 mg(10%) 18.41 0.60 2 4-BrBn c-PrCH₂ H Me 3 mg (15%) 17.69 0.58 3 4-BrBnt-BuOOCCH₂ H Me 9 mg (41%) 18.28, 18.59 0.59 4 2-CNBn c-PrCH₂ H Me 4 mg(23%) 15.81 0.28 5 2-CNBn t-BuOOCCH₂ H Me 4 mg (20%) 17.35 0.58 6 Bn EtEt Et 11 mg (64%) 18.21, 18.48 0.62, 0.68 7 Bn c-PrCH₂ H Et 6 mg (35%)16.94 0.55 8 Bn Bn H Et 10 mg (54%) 17.69, 18.03 0.60 9 Bn t-BuOOCCH₂ HEt 6 mg (31%) 17.60, 17.91 0.57 10 4-BrBn Et Et Et 5 mg (25%) 19.29,19.72 0.75 11 4-BrBn CH₃O(CH₂)₂ H Et 4 mg (19%) 19.05 0.36 12 4-BrBnc-PrCH₂ H Et 4 mg (20%) 18.04 0.70 13 4-BrBn t-BuOOCCH₂ H Et 6 mg (30%)18.97, 19.33 0.72 14 2-CNBn Bn H Et 5 mg (26%) 17.13, 17.34 0.60 152-CNBn CH₃O(CH₂)₂ H Et 2 mg (11%) 13.86 0.21 16 2-CNBn c-PrCH₂ H Et 5 mg(28%) 16.30, 16.53 0.59 17 2-CNBn r-BuOOCCH₂ H Et 5 mg (25%) 17.04,17.23 0.66 18 Bn Et Et i-Pr 9 mg (51%) 17.79, 17.96 0.74 19 Bn Bn H i-Pr10 mg (53%) 18.36, 18.65 0.72 20 Bn CH₃O(CH₂)₂ H i-Pr 3 mg (17%) 15.84,16.21 0.43 21 Bn c-PrCH₂ H i-Pr 10 mg (57%) 17.63, 17.94 0.70 22 Bnt-BuOOCCH₂ H i-Pr 8 mg (40%) 18.22, 18.51 0.74 23 4-BrBn Et Et i-Pr 3 mg(15%) 20.48, 20.68 0.48 24 4-BrBn CH₃O(CH₂)₂ H i-Pr 5 mg (24%) 19.26,19.70 0.11 25 4-BrBn c-PrCH₂ H i-Pr 3 mg (15%) 19.10 0.49 26 4-BrBnt-BuOOCCH₂ H i-Pr 12 mg (52%) 19.26, 19.50 0.50 27 2-CNBn Bn H i-Pr 6 mg(30%) 17.79, 17.94 0.66 28 2-CNBn c-PrCH₂ H i-Pr 5 mg (27%) 17.03, 17.180.64 29 2-CNBn t-BuOOCCH₂ H i-Pr 5 mg (24%) 16.23 0.66

By activation with isocyanates (variant B), the following compounds ofthe formula B are obtained

B

R⁷ R₂ Yield R_(T) ^(b)) R_(F) ^(b)) 1 4-ClPh Me 5 mg 18.75 0.20; 0.16 22-CF₃Ph Me 5 mg (30%) 18.94 0.31; 0.26 3 2-NO₂Ph Me 5 mg (31%) 18.800.30; 0.26 4 4-CN-Ph Me 3 mg (20%) 13.93 0.06 5 3,4-Cl₂Ph Me 4 mg (26%)19.35 0.20; 0.14 6 4-ClPh Me 5 mg (31%) 16.53 0.34 7 2-CF₃Ph Me 5 mg(29%) 17.63 0.46 8 2-NO₂Ph Me 9 mg (54%) 16.36 0.46 9 4-CN-Ph Me 4 mg(25%) 14.75 0.13 10 3,4-Cl₂Ph Me 5 mg (29%) 17.84 0.29 11 4-ClPh Me 9 mg(48%) 21.35 0.63 12 2-CF₃Ph Me 14 mg (69%) 21.27 0.61 13 2-NO₂Ph Me 11mg (57%) 21.08 0.70 14 4-CN-Ph Me 5 mg (32%) 20.04 0.36 15 3,4Cl₂Ph Me 7mg (35%) 23.38 0.63 16 4-ClPh Me 5 mg (23%) 19.90; 20.05 0.30 17 2-CF₃PhMe 10 mg (43%) 19.49 0.40 18 2-NO₂Ph Me 9 mg (41%) 19.78; 19.88 0.39 194-CN-Ph Me 3 mg (14%) 18.53; 18.64 0.13 20 3,4Cl₂Ph Me 9 mg (39%) 20.65;20.95 0.34; 0.26 21 4-ClPh Me 4 mg 16.12; 16.92 0.29; 0.21 22 2-CF₃Ph Me7 mg (34%) 20.72 0.33 23 2-NO₂Ph Me 6 mg (30%) 17.83 0.31 24 4-CN-Ph Me3 mg 14.46 0.10 25 3,4-Cl₂Ph Me 4 mg (19%) 19.26; 19.69 0.24 26 4-ClPhEt 4 mg (25%) 18.98 0.29 27 2-CF₃Ph Et 5 mg (29%) 15.93; 16.09 0.42 282-NO₂Ph Et 4 mg (24%) 14.49 0.40 29 4-CN-Ph Et 3 mg 12.21 0.15 303,4-Cl₂Ph Et 4 mg (23%) 19.69; 19.90 0.33 31 4-ClPh Et 4 mg (24%) 17.260.54 32 2-CF₃Ph Et 8 mg (44%) 16.79 0.38 33 2-NO₂Ph Et 7 mg (41%) 17.240.55 34 4-CN-Ph Et 4 mg (24%) 15.55 0.27 35 3,4-Cl₂Ph Et 4 mg (22%)18.63 0.46 36 4-ClPh Et 9 mg (46%) 21.91; 22.07 0.75 37 2-CF₃Ph Et 11 mg(53%) 20.99; 21.16 0.71; 0.64 38 2-NO₂Ph Et 9 mg (45%) 22.14 0.80 394-CN-Ph Et 6 mg (31%) 20.64; 20.79 0.57 40 3,4-Cl₂Ph Et 8 mg (38%) 22.280.77 41 4-ClPh Et 4 mg (18%) 18.98 0.46 42 2-CF₃Ph Et 10 mg (42%) 19.89;20.18 0.55 43 2-NO₂Ph Et 6 mg (27%) 20.59; 20.74 0.55 44 4-CN-Ph Et 4 mg(18%) 18.73; 19.31 0.25 45 3,4-Cl₂Ph Et 8 mg (34%) 19.39; 19.53 0.45 464-ClPh Et 6 mg (30%) 16.11 0.35 47 2-CF₃Ph Et 6 mg (29%) 20.68;21.0^(e)) 0.45; 0.36 48 2-NO₂Ph Et 6 mg (29%) 18.61 0.41 50 3,4-Cl₂Ph Et3 mg (14%) 19.68; 19.82 0.33 51 4-ClPh i-Pr 4 mg (24%) 17.12; 18.89 0.3552 2-CF₃Ph i-Pr 11 mg (61%) 21.66 0.48 53 2-NO₂Ph i-Pr 8 mg (47%) 17.160.45 55 3,4-Cl₂Ph i-Pr 4 mg (22%) 19.66 0.35 56 4-ClPh i-Pr 6 mg (35%)17.90; 18.07 0.66 57 2-CF₃Ph i-Pr 9 mg (48%) 17.60; 17.84 0.55 582-NO₂Ph i-Pr 8 mg (45%) 17.22; 18.06 0.66 59 4-CN-Ph i-Pr 4 mg (24%)16.31 0.38 60 3.4-Cl₂Ph i-Pr 4 mg (22%) 16.35 0.54 61 4-ClPh i-Pr 6 mg(30%) 22.47 0.77 62 2-CF₃Ph i-Pr 10 mg (47%) 22.15; 22.39 0.71; 0.64 632-NO₂Ph i-Pr 9 mg (44%) 22.61; 22.92 0.79 64 4-CN-Ph i-Pr 5 mg (25%)21.25 0.59 65 3,4-Cl₂Ph i-Pr 7 mg (36%) 23.47 0.80 66 4-ClPh i-Pr 7 mg(31%) 21.04 0.52 67 2-CF₃Ph i-Pr 10 mg (42%) 23.71^(e)) 0.62 68 2-NO₂Phi-Pr 8 mg (34%) 21.30 0.57 69 4-CN-Ph i-Pr 7 mg (31%) 22.43; 22.5^(e))0.43; 0.33 70 3,4-Cl₂Ph i-Pr 10 mg (41%) 21.72 0.60; 0.52 72 2-CF₃Phi-Pr 6 mg (27%) 23.78^(e)) 0.47; 0.41 73 2-NO₂Ph i-Pr 6 mg (28%)22.16^(e)) 0.54; 0.50 74 4-CN-Ph i-Pr 3 mg (15%) 16.78^(e)) 0.29 753,4-Cl₂Ph i-Pr 7 mg (32%) 23.13^(e)) 0.48; 0.42 76 4-Br-Ph Me 4 mg (19%)15.29; 15.73 0.27 77 Pr Me 5 mg (30%) 17.27 0.16 79 3-F-Ph Me 4 mg (21%)16.92; 17.06 0.25 80 EtOOCCH₂ Me 4 mg (22%) 17.28 0.09 81 4-Br-Ph Et 4mg (18%) 18.98 0.45 82 Pr Et 5 mg (29%) 16.02; 19.41 0.25 83 t-Bu Et 4mg (22%) 17.72 0.46 84 3-F-Ph Et 4 mg (21%) 19.35 0.48 85 EtOOCCH₂ Et 4mg (21%) 17.99 0.21 86 4-Br-Ph i-Pr 3 mg (13%) 19.44 0.48 87 Pr i-Pr 5mg (28%) 16.84 0.32 88 t-Bu i-Pr 3 mg (16%) 13.65 0.48 89 3-F-Ph i-Pr 3mg (15%) 19.90 0.55; 0.48 90 EtOOCCH₂ i-Pr 2 mg (10%) 19.16^(e)) 0.50^(a))Column B, grad. 2; ^(b))Petroleum ether/ethyl acetate (2:1);^(e))Column B, grad. 3 Column B: Beckmann unit (Gold System), Nucleosil100-5 C18 column measured at 220 and 254 nm Grad. 2 = CH₃CN:H₂O 10:90 -90 - 10, flow 1 ml/min, 0.1% TFA Grad. 3 = CH₃CN:H₂O 10:90 - 90 - 10,flow 0.65 ml/min, 0.1% TFA

Example 79 Functionalization of the 1-, 2-, 4- and 6-position

The following compounds are obtained:

R² R⁷ R⁶ R¹ Yield (%) 38-1 Pr o-NO₂Ph o-CF₃Ph Me 20^(a)) 38-2 p-BrBnc-PrCH₂ o-NO₂Ph Et 15 38-3 Hep p-CN-Bn o-CF₃Ph i-Pr  6 39-1 p-tBuBnCH₂COOtBu p-ClPh Me 14

Example 80 Methyl4-S-(2′-O-Acetyl-3′-O-benzyl-6′-O-tert-butyldiphenylsilyl-β-D-galactopyranosyl)-4-mercaptobutyrate

A mixture of 4.0 g (6.9 mmol) of Example compound 14a and 2.1 g (8.32mmol) of dibutyltin oxide in 50 ml of benzene is heated under reflux for2 h in a water separator. 25 ml of benzene are then removed bydistillation and the mixture is treated with 3.1 g (8.3 mmol) oftetrabutylammonium bromide and 1.4 ml (11.8 mmol) of benzyl bromide. Thesolution is stirred at 50° C. for 16 h and then largely concentrated invacuo. It is taken up in 50 ml of dichloromethane and washed three timeswith 10 ml of water each time. After drying over magnesium sulfate, thesolvent is removed in vacuo. The crude product is purified bychromatography on silica gel (column 20×5 cm, eluent petroleumether/ethyl acetate 4:1).

Yield 2.66 g (58%), yellowish oil, [α]_(D) ²⁵=+3.0° (c=1, CHCl₃);R_(F)=0.25 (petroleum ether/ethyl acetate 4:1).

Example 81 MethylS-(2′-O-Acetyl-3′-O-benzyl4′-O-[1″-(R/S)-ethoxyethyl]-6′-Otert-butyldiphenylsilyl-β-D-galactopyranosyl)-4-mercaptobutyrate

A solution of 2.58 g (3.86 mmol) of Example compound 80 in 100 ml ofdichloromethane is stirred at room temp. for 4 h after addition of 50 mlof ethyl vinyl ether and 0.49 g (1.93 mmol) of pyridiniump-toluenesulfonate. The mixture is poured into satd sodiumhydrogencarbonate solution and the aqueous phase is extracted with ethylacetate. The combined organic phases are then dried over magnesiumsulfate and freed from the solvent in vacuo. Purification is carried outby chromatography on silica gel (column 15×3 cm, eluent petroleumether/ethyl acetate 4:1).

Yield 1.25 g (45%), yellowish oil, [α]_(D) ²⁵=−13.3° (c=1, CHCl₃);R_(F=0.22) (petroleum ether/ethyl acetate 4:1).

Example 82 MethylS-(3′-O-benzyl4′-O-[1″-(R/S)-ethoxyethyl]-6′-O-tert-butyldiphenylsilyl-β-D-galactopyranosyl)4-mercaptobutyrate,Polymer-bound

According to the general working procedure, 1.45 g (1.60 mmol) ofaminomethyl polystyrene are loaded with 1.25 g (1.69 mmol) of Examplecompound 81.

Loading according to sulfur content of the elemental analysis: 0.61mmol/g.

Example 83 Functionalization of the 1, 2, 3, 4 and 6-position

The following compounds are obtained:

R² R⁵ R⁶ R⁷ R¹ Yield (%) 41-1 p-tBuBn 2 × Et (from Et₂NH) p-Cl-Pho-NO₂Ph Me 23 41-2 Hep o-NO₂Ph o-CF₃Ph p-CN-Ph Me 16* 41-3 p-BrBnm,p-Cl₂Ph o-CF₃Ph p-Cl-Ph i-Pr  5 42-1 p-BrBn Hep o-NO₂Ph p-Cl-Ph Me 3842-2 p-tBuBn Bu o-NO₂Ph p-CN-Ph i-Pr  4 42-3 Bn CH₂COOtBu o-NO₂Php-Cl-Ph Me  6 *) Minor component (according to chromatography)

Example 84S-(3′-O-Allyl4′-O-[1″-(R/S)-ethoxyethyl]-6′-O-tert-butyldiphenylsilyl-β-D-galactopyranosyl)-4-mercaptobutyricAcid, Polymer-bound (40)

8.60 g (9.5 mmol) of aminomethylpolystyrene are loaded with 6.70 g (10.0mmol) of 21 (Ex. 14c) according to the general procedure. Loadingaccording to sulfur content of the elemental analysis: 0.93 mmol/g.

What is claimed is:
 1. A compound of the formula II, where formula II ischosen from formula IIa, IIb, and IIc:

and wherein R¹ is a group of the formula III(C₁-C₆)-alkylene-[N—C(O)]_(n)—[(C₆-C₁₂)-arylene]_(p)—(C₀-C₆)-alkylene-C(O)R⁹  (III) in which n and p are 0 or 1, where p and n cannot simultaneously be 1;R² in the case in which X is equal to O, is acetyl or banzoyl; in thecase in which X is equal to N is a phthaloyl protective group, DDE(1-(4,4-dimethyl-2,6-dioxocyclohexylideneethyl) or NDE(2-acetyl-4-nitroindan-1,3-dione); R³ is an allyl protective group; R⁴is ethoxy or SEM (2-(trimethylsilyl)ethoxymethyl); R⁵ istert-butyidimethylsilyl or tert-butyldiphenylsilyl; R⁹ is OR¹⁰ orNR¹¹R¹¹, where R¹⁰ is H, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-(C₆-C₁₂)-aryl, andR¹¹ independently of one another is H, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-(C₆-C₁₂)-aryl or a polymeric solid support; Y is O or S;and X is O or N.
 2. A compound of the formula II, where formula II ischosen from formula IIa, IIb, and IIc:

and wherein R¹ is a linker group which can be linked via a covalent bondto a carrier functionalized by a heteroatom; R² is a phthaloylprotective group, DDE (1-(4,4-dimethyl-2,6-dioxocyclohexylideneethyl) orNDE (2-acetyl-4-nitroindan-1,13-dione); R³ is an allyl protective group;R⁴ is ethoxy or SEM (2-(trimethylsilyl)ethoxymethyl); R⁵ istert-butyldimethylsilyl or tert-butyldiphenylsilyl; Y is S; and X is N.